Trilipix 45 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRILIPIX® 45 MG (TRILIPIX® 45 MG) TRILIPIX® 135 MG (TRILIPIX® 135 MG)

Composition:

Active substance: fenofibrate choline;

1 capsule contains 59.6 mg or 178.8 mg of fenofibrate choline (equivalent to 45 mg or 135 mg of fenofibric acid);

Excipients: hypromellose, povidone, hydroxypropyl cellulose, anhydrous colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer (type C) dispersion, talc, triethyl citrate, purified water;

Capsule shell: for 45 mg capsules: iron oxide yellow (E 172), iron oxide black (E 172), iron oxide red (E 172), titanium dioxide (E 171), gelatin;

for 135 mg capsules: iron oxide yellow (E 172), titanium dioxide (E 171), indigo carmine (E 132), gelatin;

BLACK SW-9008/SW-9009 ink: shellac (E 904), anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, concentrated ammonia solution, potassium hydroxide, iron oxide black (E 172);

WHITE SB-0007P ink: shellac (E 904), anhydrous ethanol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, titanium dioxide (E 171).

Pharmaceutical form. Modified release capsules.

Main physicochemical properties:

Trilipix 45 mg

Size 3 capsule with an opaque cap ranging from reddish-brown to orange-brown and an opaque yellow body. The corporate logo of Abbott is printed on the cap in white ink. The number "45" is printed on the body in black ink.

Trilipix 135 mg

Size 0 capsule with an opaque blue cap and an opaque yellow body. The corporate logo of Abbott is printed on the cap in white ink. The number "135" is printed on the body in black ink.

Pharmacotherapeutic group. Hypolipidemic agents, single-component, fibrates.
ATC code C10AB11.

Pharmacological Properties

Pharmacodynamics

The active component of Trilipix is fenofibric acid. The lipid-modifying effect of fenofibric acid observed in clinical practice is explained by stimulation of peroxisome proliferator-activated receptor alpha (PPARα). Through this mechanism, fenofibric acid increases lipolysis and clearance of triglyceride-rich plasma particles by activating lipoprotein lipase and reducing the synthesis of Apo CIII (an inhibitor of lipoprotein lipase activity).

The resulting reduction in TG levels leads to a change in the size and composition of VLDL particles from small, dense particles (which are considered atherogenic due to susceptibility to oxidation) to larger, more active particles. These larger particles have higher affinity for cholesterol receptors and are rapidly catabolized. Activation of PPARα also increases the synthesis of HDL-C and Apo AI and AII.

Elevated levels of total cholesterol, LDL-C, and Apo B, and reduced levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis in humans. Epidemiological studies have demonstrated that cardiovascular disease and mortality are directly proportional to levels of total cholesterol, LDL-C, and TG, and inversely proportional to HDL-C levels. The independent effect of increasing HDL-C or reducing TG on cardiovascular disease risk and mortality has not been established.

Pharmacokinetics

Trilipix contains fenofibric acid, which is the only pharmacologically active circulating component in plasma following oral administration of Trilipix. Fenofibric acid is also the pharmacologically active circulating component in plasma following oral administration of fenofibrate, the ester derivative of fenofibric acid.

Plasma concentrations of fenofibric acid following administration of 135 mg Trilipix capsules with modified release are equivalent to those observed after administration of a 200 mg micronized fenofibrate capsule taken with food.

Absorption: Fenofibric acid is well absorbed from the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%.

Maximum plasma levels of fenofibric acid are observed within 4 to 5 hours after a single dose of Trilipix on an empty stomach.

Exposure to fenofibric acid in plasma, assessed by Cmax and AUC, does not differ significantly between administration of a single 135 mg dose of Trilipix on an empty stomach or in the fed state.

Distribution: After repeated administration of Trilipix, plasma levels of fenofibric acid reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those after a single dose. Protein binding in serum in subjects with or without dyslipidemia is approximately 99%.

Metabolism: Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to form a benzhydrol metabolite, which in turn is conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data obtained after administration of fenofibrate indicate that fenofibric acid is largely not subject to oxidative metabolism (e.g., by cytochrome P450).

Elimination: Following absorption, Trilipix is primarily excreted in urine as fenofibric acid and fenofibric acid glucuronide.

Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once-daily administration of Trilipix.

Special Populations

Elderly individuals: The same dose of Trilipix can be administered to elderly individuals with normal renal function without increased accumulation of the drug or its metabolites.

Renal impairment: Trilipix should be avoided in patients with severe renal impairment, and dose reduction is required in patients with mild to moderate renal impairment.

Clinical characteristics.

Indications.

TriLipix is indicated as an adjunct to diet:

• in combination with statins to reduce triglyceride (TG) levels and increase high-density lipoprotein cholesterol (HDL-C) levels in patients with mixed dyslipidemia and ischemic heart disease (IHD) or IHD risk equivalents (other clinical forms of atherosclerosis: peripheral artery disease, abdominal aortic aneurysm, and symptomatic carotid artery disease; diabetes; multiple risk factors reflecting a 10-year IHD risk > 20%), who are receiving optimal statin therapy to achieve low-density lipoprotein cholesterol (LDL-C) target levels;
• to reduce TG in patients with severe hypertriglyceridemia;
• to reduce elevated LDL-C, total cholesterol, triglycerides, and apolipoprotein B, and to increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia.

Contraindications.

• Severe renal impairment (creatinine clearance < 30 mL/min);
• liver disease (including biliary cirrhosis and unexplained persistent liver function abnormalities) and hepatic failure;
• gallbladder disease;
• chronic or acute pancreatitis, except acute pancreatitis due to severe hypertriglyceridemia;
• known photosensitivity or phototoxic reaction during treatment with fibrates or ketoprofen;
• hypersensitivity to the active substance (fenofibric acid, choline fenofibrate), fenofibrate, or to any of the excipients;
• pediatric population (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Caution should be exercised when TriLipix is used concomitantly with oral coumarin anticoagulants. TriLipix may potentiate the anticoagulant effect of these agents, leading to prolonged prothrombin time/international normalized ratio (INR). To prevent complications related to bleeding, frequent monitoring of prothrombin time/INR is recommended, and dosage adjustment of the oral anticoagulant should be made until prothrombin time/INR is stabilized.

Cyclosporine

Since cyclosporine may cause manifestations of nephrotoxicity, including reduced creatinine clearance and increased serum creatinine, and because renal excretion is the major elimination pathway for fibrate-class drugs, including TriLipix, there is a risk that the interaction may lead to decreased renal function. The benefits and risks of using TriLipix with immunosuppressants and other potentially nephrotoxic agents should be carefully evaluated, and the lowest effective dose should be used.

Statins

The risk of serious muscle toxicity may increase when fenofibrate or fenofibric acid is used concomitantly with HMG-CoA reductase inhibitors. Such combination therapy should be used with caution, and careful monitoring of patients for possible signs of muscle toxicity is required (see section "Special precautions"). Specific studies in healthy volunteers have shown no clinically significant pharmacokinetic interactions with lipid-lowering agents such as HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) and ezetimibe; however, pharmacodynamic interactions cannot be excluded. Therefore, dose adjustment of TriLipix or concomitantly administered drugs is not required.

Oral hypoglycemic agents

In healthy volunteers, no clinically significant pharmacokinetic interactions between fenofibrate or fenofibric acid and rosiglitazone, metformin, or glimepiride have been demonstrated. Dose adjustment of TriLipix or concomitantly administered drugs is not required.

Glitazones

There have been reports of some reversible paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) levels during concomitant use of fenofibrate and glitazones. In such cases, monitoring of HDL-C levels is recommended, and therapy should be discontinued if HDL-C levels become too low.

Gastrointestinal agents

In healthy volunteers, no clinically significant pharmacokinetic interactions between fenofibrate or fenofibric acid and omeprazole have been demonstrated.

Cytochrome P450 enzyme system

In vitro studies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. At therapeutic concentrations, it is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and a weak to moderate inhibitor of CYP2C9.

Special precautions for use.

Skeletal muscles

Monotherapy with fibrates or statins increases the risk of myositis or myopathy and is associated with rhabdomyolysis. Observational data indicate that the risk of rhabdomyolysis increases when fibrates are used concomitantly with statins. For information on important drug interactions that increase statin levels and may lead to an increased risk, refer to the respective statin product information. The risk of serious muscle toxicity is increased in elderly patients and in patients with diabetes, renal impairment, and hypothyroidism.

Myopathy should be considered in any patient presenting with diffuse myalgia, muscle tenderness or weakness, and/or markedly elevated levels of creatine phosphokinase (CPK). Patients should promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. In patients reporting these symptoms, CPK levels should be assessed, and if markedly elevated CPK levels (more than 5 times the upper limit of normal range) or myopathy/myositis are present, treatment with TriLipix and statins should be discontinued.

Renal function

Reversible increases in serum creatinine levels have been reported in patients receiving TriLipix as monotherapy or in combination with statins, as well as in patients receiving fenofibrate. Increases in serum creatinine were generally stable over time without evidence of progressive increases during long-term therapy and tended to return to baseline levels after discontinuation of treatment. The clinical significance of these observations is unknown. Monitoring of renal function is recommended in patients with renal impairment who are taking TriLipix. Monitoring may also be required in patients at increased risk of renal failure (elderly patients and those with diabetes). Treatment should be discontinued if serum creatinine levels increase by more than 50% above the upper limit of normal. Measurement of creatinine levels is recommended within the first 3 months of starting treatment and periodically thereafter.

Hepatic function

Use of TriLipix at a dose of 135 mg once daily, either as monotherapy or in combination with low or moderate doses of statins, has been associated with increased serum transaminase levels (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)). Cases of hepatocellular, chronic active, and cholestatic hepatitis have been reported after exposure ranging from weeks to several years. Cirrhosis has been reported very rarely as a consequence of chronic active hepatitis.

Regular monitoring of liver function, including serum ALT and AST levels, should be performed periodically during TriLipix therapy, and treatment should be discontinued if enzyme levels persistently exceed the upper limit of normal by more than three times.

Pancreatitis

Pancreatitis has been reported in patients receiving fibrate-class medications, including TriLipix. These observations may reflect inadequate efficacy of the drugs in patients with severe hypertriglyceridemia, a direct drug effect, or secondary phenomena mediated by gallstone formation or biliary sludge leading to obstruction of the common bile duct.

Use during pregnancy or breastfeeding.

Pregnancy.

There are insufficient data on the use of the drug in pregnant women.

Animal studies have not demonstrated teratogenic effects.

Embryotoxic effects were observed at doses within the range of maternal toxicity. The potential risk to humans is unknown. Therefore, TriLipix should be used during pregnancy only after careful assessment of the benefit-risk ratio.

Breastfeeding.

It is unknown whether fenofibrate and/or its metabolites are excreted in human breast milk. Risk to the breastfed infant cannot be excluded. Therefore, fenofibrate should not be used during breastfeeding.

Fertility.

There are no clinical data on the effect of the drug on fertility. Reversible effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery.

TriLipix has no effect or a negligible effect (dizziness) on the ability to drive or operate machinery.

Method of administration and dosage

Before initiating Trilipix as monotherapy or in combination with statins, patients should be placed on an appropriate lipid-lowering diet, which must be maintained throughout the course of treatment.

Trilipix modified-release capsules may be taken independently of food.

Serum lipids should be monitored periodically.

The maximum dose is 135 mg once daily.

Adults

Combination therapy with statins for the treatment of mixed dyslipidemia

Trilipix 135 mg may be used concomitantly with an HMG-CoA reductase inhibitor (statin) in patients with mixed dyslipidemia. For convenience, the daily dose of Trilipix may be taken simultaneously with the statin, according to the dosing recommendations for each agent. Concomitant use with the maximum statin dose has not been evaluated in clinical studies and should be avoided unless the potential benefit outweighs the risk.

Monotherapy

-Severe hypertriglyceridemia

The initial dose of Trilipix is 45 to 135 mg once daily. Dosage should be individualized according to patient response and, if necessary, adjusted after repeat lipid measurements taken every 4 to 8 weeks. The maximum dose is 135 mg once daily.

-Primary hyperlipidemia or mixed dyslipidemia

The dose of Trilipix is 135 mg once daily.

Elderly patients

Dosage for elderly patients should be based on renal function.

Patients with renal impairment

Treatment with Trilipix should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min). The dose may be increased only after assessment of renal function and evaluation of lipid levels at this dose. Trilipix should be avoided in patients with severe renal impairment.

Patients with hepatic impairment

Patients with liver disease have not been studied.

Children

Trilipix is not recommended for use in children under 18 years of age due to lack of safety and efficacy data.

Overdose

There is no specific antidote for Trilipix overdose. In case of overdose, general supportive measures should be employed, including monitoring of vital signs and observation of the patient's clinical status. If indicated, elimination of the unabsorbed drug may be achieved by inducing emesis or gastric lavage; standard precautions should be taken to protect the airway. Since Trilipix is highly protein-bound, hemodialysis is not indicated.

Adverse reactions.

Monotherapy.

Adverse reactions that occurred in 3% or more of patients during randomized controlled trials of Trilipix treatment are listed in the table below [number (%)].

Concomitant use with statins (double-blind controlled studies)

Adverse reactions that occurred in 3% or more of patients receiving Trilipix treatment concomitantly with statins during randomized controlled trials are listed in the table below [number (%)].

Adverse reaction	Trilipix (n=490)	Low-dose statins* (n=493)	Trilipix + low-dose statins* (n=490)	Medium-dose statins** (n=491)	Trilipix + medium-dose statins** (n=489)	High-dose statins*** (n=245)
Gastrointestinal disorders
Constipation	16 (3.3)	11 (2.2)	16 (3.3)	13 (2.6)	15 (3.1)	6 (2.4)
Diarrhea	19 (3.9)	16 (3.2)	15 (3.1)	24 (4.9)	18 (3.7)	17 (6.9)
Dyspepsia	18 (3.7)	13 (2.6)	13 (2.7)	17 (3.5)	23 (4.7)	6 (2.4)
Nausea	21 (4.3)	18 (3.7)	17 (3.5)	22 (4.5)	27 (5.5)	10 (4.1)
General disorders and administration site conditions
Fatigue	10 (2.0)	13 (2.6)	13 (2.7)	13 (2.6)	16 (3.3)	5 (2.0)
Pain	17 (3.5)	9 (1.8)	16 (3.3)	8 (1.6)	7 (1.4)	8 (3.3)
Infections and infestations
Nasopharyngitis	17 (3.5)	29 (5.9)	23 (4.7)	16 (3.3)	21 (4.3)	9 (3.7)
Sinusitis	16 (3.3)	4 (0.8)	14 (2.9)	8 (1.6)	17 (3.5)	4 (1.6)
Upper respiratory tract infection	26 (5.3)	13 (2.6)	18 (3.7)	23 (4.7)	23 (4.7)	7 (2.9)
Investigations
Increased ALT levels	6 (1.2)	2 (0.4)	15 (3.1)	2 (0.4)	12 (2.5)	4 (1.6)
Musculoskeletal and connective tissue disorders
Arthralgia	19 (3.9)	22 (4.5)	21 (4.3)	21 (4.3)	17 (3.5)	12 (4.9)
Back pain	31 (6.3)	31 (6.3)	30 (6.1)	32 (6.5)	20 (4.1)	8 (3.3)
Muscle spasms	8 (1.6)	18 (3.7)	12 (2.4)	24 (4.9)	15 (3.1)	6 (2.4)
Myalgia	16 (3.3)	24 (4.9)	17 (3.5)	23 (4.7)	15 (3.1)	15 (6.1)
Limb pain	22 (4.5)	24 (4.9)	14 (2.9)	21 (4.3)	13 (2.7)	9 (3.7)
Nervous system disorders
Dizziness	20 (4.1)	8 (1.6)	19 (3.9)	11 (2.2)	16 (3.3)	2 (0.8)
Headache	62 (12.7)	64 (13.0)	64 (13.1)	82 (16.1)	58 (11.9)	32 (13.1)

*Statins at low dose: rosuvastatin 10 mg, simvastatin 20 mg or atorvastatin 20 mg.

**Statins at moderate dose: rosuvastatin 20 mg, simvastatin 40 mg or atorvastatin 40 mg.

***Statins at high dose: rosuvastatin 40 mg, simvastatin 80 mg or atorvastatin 80 mg.

Concomitant use with statins (long-term treatment up to 64 weeks).

Patients who successfully completed any of the three double-blind controlled trials participated in a long-term study lasting 52 weeks, during which they received Trilipix concomitantly with moderate-dose statins. All patients (2201) received at least one dose of Trilipix concomitantly with a statin in either a double-blind controlled trial or the long-term study, where treatment lasted up to 64 weeks.

Additional adverse reactions (not listed in the table) observed in 3% or more patients receiving Trilipix in combination with statins during the double-blind controlled trials or the long-term study are listed below.

Infections and infestations: bronchitis, influenza, urinary tract infection.

Investigations: increased levels of AST, CK in blood, and liver enzymes.

Musculoskeletal and connective tissue disorders: musculoskeletal pain.

Psychiatric disorders: insomnia.

Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain.

Vascular disorders: arterial hypertension.

Fenofibrate

Fenofibric acid is the active metabolite of fenofibrate. The following adverse reactions were observed during placebo-controlled clinical trials with fenofibrate (n=2344), with frequencies defined as follows: very common (≥1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000), including isolated reports.

Blood and lymphatic system disorders: rare – decreased hemoglobin, decreased leukocyte count.

Immune system disorders: rare – hypersensitivity (including anaphylactic reaction).

Nervous system disorders: uncommon – headache.

Vascular disorders: uncommon – thromboembolism (pulmonary embolism, deep vein thrombosis)* *.

Gastrointestinal disorders: common – gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea, flatulence); uncommon – pancreatitis*.

Hepatobiliary disorders: common – increased transaminase levels; uncommon – gallstones; rare – hepatitis.

Skin and subcutaneous tissue disorders: uncommon – skin hypersensitivity (e.g., rash, pruritus, urticaria); rare – alopecia, photosensitivity reactions.

Musculoskeletal and connective tissue disorders: uncommon – muscle disorders (e.g., myalgia, myositis, muscle spasms, weakness).

Reproductive system and breast disorders: uncommon – sexual dysfunction.

Investigations: very common – increased blood homocysteine level***; uncommon – increased blood creatinine level; rare – increased blood urea level.

*In the FIELD randomized placebo-controlled trial conducted in 9795 patients with type 2 diabetes, a statistically significant increase in pancreatitis was observed in patients receiving fenofibrate compared to placebo (0.8% vs. 0.5%; p=0.031);

**A statistically significant increase in pulmonary embolism (0.7% in placebo group vs. 1.1% in fenofibrate group; p=0.022) and a statistically non-significant increase in deep vein thrombosis (placebo: 1.0% [48/4900 patients] vs. fenofibrate: 1.4% [67/4895 patients]; p=0.074) were reported;

***The mean increase in blood homocysteine level in patients receiving fenofibrate was 6.5 µmol/L and was reversible after discontinuation of fenofibrate. The elevated risk of venous thromboembolic events may be associated with increased homocysteine levels. The clinical significance of this is unclear.

In addition to events reported during clinical trials, the following adverse reactions have been observed during post-marketing use of fenofibrate. Based on available data, the exact frequency cannot be estimated and is therefore classified as "unknown".

Respiratory, thoracic and mediastinal disorders: interstitial lung disease.

Musculoskeletal and connective tissue disorders: rhabdomyolysis.

Hepatobiliary disorders: jaundice, complications of cholelithiasis (e.g., cholecystitis, cholangitis, biliary colic).

Nervous system disorders: fatigue.

Skin and subcutaneous tissue disorders: severe skin reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Shelf life. 2.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, out of the reach of children.

Packaging. 10 capsules per blister, 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Mylan Laboratories SAS, France / Mylan Laboratories SAS, France.

Manufacturer's address and location of its business operations.

Route de Belleville, Lieu-dit Maillard, 01400, Chatillon-sur-Chalaronne, France / Route de Belleville, Lieu-dit Maillard, 01400, Chatillon-sur-Chalaronne, France.