Tredaptive^® (Tablets) Instructions for Use

Marketing Authorization Holder

Merck Sharp & Dohme, B.V. (Netherlands)

Manufactured By

MSD Technology Singapore PTE, Ltd. (Singapore)

Labeled By

MERCK SHARP & DOHME, Ltd. (United Kingdom)

Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

ATC Code

C10AD52 (Nicotinic acid in combination with other drugs)

Active Substances

Nicotinic acid (Rec.INN registered by WHO)

Laropiprant (Rec.INN registered by WHO)

Dosage Form

Tredaptive®

Modified-release tablets 1000 mg+20 mg: 14, 28, 56, 84 or 98 pcs.

Dosage Form, Packaging, and Composition

Modified-release tablets from white to almost white, oblong, biconvex, bilayer, imprinted with “552” on one side; white to almost white on the break.

Excipients : nicotinic acid layer hypromellose 2208 – 75 mg, colloidal silicon dioxide – 6.25 mg, sodium stearyl fumarate – 18.75 mg, microcrystalline cellulose – 150 mg; laropiprant layer hypromellose – 9 mg, microcrystalline cellulose – 128.4 mg, croscarmellose sodium – 12 mg, lactose monohydrate – 128.4 mg, magnesium stearate – 0.75 mg, sodium stearyl fumarate – 1.5 mg.

14 pcs. – PVC/Aclar-Aluminum blisters (1) – cardboard packs.
14 pcs. – PVC/Aclar-Aluminum blisters (2) – cardboard packs.
14 pcs. – PVC/Aclar-Aluminum blisters (4) – cardboard packs.
14 pcs. – PVC/Aclar-Aluminum blisters (6) – cardboard packs.
14 pcs. – PVC/Aclar-Aluminum blisters (7) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent

Pharmacological Action

The drug Tredaptive^® is a combination drug containing the active substances: nicotinic acid, which in doses > 1000 mg/day is a hypolipidemic agent, and Laropiprant, a potent selective antagonist of the prostaglandin D2 (PGD₂) receptor subtype 1 (DP₁).

Nicotinic acid in lipid-lowering doses reduces the concentration of low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B, the main protein of LDL), triglycerides (TG), and lipoprotein (a) (Lp(a), a modified LDL particle), and also increases the concentration of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I, the main protein component of HDL).

Laropiprant suppresses PGD2-induced flushing of the skin of the head, neck, and upper body that accompanies the intake of nicotinic acid in lipid-lowering doses. Laropiprant does not affect lipid concentrations and does not affect the pharmacodynamics of nicotinic acid.

Mechanism of action

Nicotinic acid The mechanisms by which Nicotinic acid modifies the plasma lipid profile are not fully understood. Nicotinic acid in lipid-lowering doses inhibits the release of free fatty acids from adipocytes of adipose tissue and transiently reduces their plasma concentration. Free fatty acids (FFA) are further taken up by hepatocytes for further synthesis of triglycerides as part of VLDL-C, which, under conditions of reduced amounts of free FFA, is accompanied by a decrease in the final amount of synthesized VLDL-C and apo B. Since LDL-C is formed as a result of VLDL catabolism, a decrease in the amount of VLDL-C produced by the liver may be accompanied by a decrease in plasma concentrations of LDL-C and total cholesterol. In addition to this mechanism, the main pathways for reducing TG concentration may be nicotinic acid-mediated suppression of de novo lipogenesis, as well as suppression of the esterification process, i.e., the formation of triglycerides from fatty acids in hepatocytes.

Laropiprant Flushing of the skin of the head, neck, and upper body caused by taking nicotinic acid in lipid-lowering doses is due to the release of prostaglandin D₂ in the skin. Two subtypes of G-protein-coupled prostaglandin D₂ receptors are known – DP₁ and DP₂. Results from experimental genetic and pharmacological studies indicate that DP₁ receptors are involved in nicotinic acid-induced peripheral vasodilation. Unlike acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs), which non-selectively inhibit the production of many prostaglandins, Laropiprant is a selective antagonist only of prostaglandin PGD₂, suppressing nicotinic acid-induced flushing of the skin of the head, neck, and upper body by selectively blocking the action of prostaglandin D₂ on DP₁ receptors.

Effect of nicotinic acid on lipids

Clinical and epidemiological data indicate that high concentrations of TC, LDL-C, apo B, and TG contribute to the formation of atherosclerotic vascular lesions and are a risk factor for the development of cardiovascular diseases. Conversely, high concentrations of HDL-C and apo A-I reduce the risk of developing cardiovascular diseases. Reducing LDL cholesterol leads to a reduction in the risk of developing cardiovascular diseases.

An increase in the HDL₂ : HDL₃ fraction ratio also reduces the risk of developing cardiovascular diseases. It is assumed that HDL is involved in the reverse transport of cholesterol from tissues to the liver, suppresses inflammation in the vascular wall caused by the atherosclerotic process, and also has antioxidant and antithrombotic effects.

Lipoproteins enriched with cholesterol and triglycerides, including VLDL, intermediate-density lipoproteins (IDL), as well as LDL, contribute to the formation and progression of atherosclerosis. Lp(a) is a modified LDL particle that also contributes to an increased risk of cardiovascular disease. Elevated plasma triglyceride concentration is often combined with low HDL-C concentration and small LDL particles and is associated with other non-lipid metabolic risk factors for coronary heart disease (CHD). Thus, plasma triglyceride concentration is not an independent risk factor for CHD. Small, dense LDL particles are considered to have the greatest atherogenic potential. Nicotinic acid in doses > 1000 mg/day reduces the concentration of LDL-C, TC, TG, VLDL-C, apo B (the main LDL) and lipoprotein (a) (Lp(a)). Nicotinic acid in lipid-lowering doses also increases the concentration of HDL-C and its main protein component – apo A-I. Nicotinic acid increases the concentration of the HDL₂ fraction to a greater extent than HDL₃, thus increasing the HDL₂:HDL₃ ratio. In addition, Nicotinic acid in lipid-lowering doses induces a shift in HDL distribution from small, dense particles to larger particles. The assessment of the clinical significance of this effect requires further research.

Laropiprant

Suppression of flushing of the skin of the head, neck, and upper body caused by nicotinic acid in lipid-lowering doses.

Flushing of the skin caused by nicotinic acid in lipid-lowering doses is due to dilation of the superficial skin vessels and is accompanied by redness, a feeling of warmth/heat, skin itching or tingling, mainly in the area of the head, neck, and upper body. Flushing of the skin is mediated mainly by prostaglandin D₂(PGD₂) released by skin cells. After a single oral dose of nicotinic acid in lipid-lowering doses, the onset of flushing of the skin of the head, neck, and upper body coincides with a significant increase in the plasma concentration of 9α,11β-PGF₂, which is a metabolite of PGD₂. The use of nicotinic acid in lipid-lowering doses is not accompanied by an increase in plasma concentrations of histamine metabolites and concentrations of the main metabolites of prostaglandin E₂ in urine.

Laropiprant is an effective and selective antagonist of the PGD₂-DP₁ receptor subtype 1. Preclinical studies have shown that the effect on these receptors is the main mechanism for the development of flushing of the skin of the head, neck, and upper body caused by the action of nicotinic acid in lipid-lowering doses. Laropiprant reduces the severity of flushing caused by nicotinic acid. The reduction in flushing (according to patient questionnaires) correlated with a reduction in vasodilation symptoms associated with the action of nicotinic acid (according to measurements of skin blood flow intensity). In a double-blind, randomized, placebo-controlled, crossover study to evaluate the additional effect of acetylsalicylic acid at a dose of 325 mg on the severity of flushing of the skin of the head, neck, and upper body caused by the use of the drug Tredaptive^® (2000 mg/40 mg), 77 healthy volunteers participated. The study was conducted in four groups according to treatment type: A – the drug Tredaptive^® (2000 mg/40 mg) with placebo; B – the drug Tredaptive^® (2000 mg/40 mg) with acetylsalicylic acid at a dose of 325 mg; C – placebo; D – the drug Tredaptive^®(1000 mg/20 mg) with acetylsalicylic acid at a dose of 325 mg. In healthy volunteers receiving the drug Tredaptive^{® ®}
(2000 mg/40 mg), preliminary administration of acetylsalicylic acid at a dose of 325 mg did not have an additional effect on reducing the severity of flushing caused by nicotinic acid in lipid-lowering doses.

Effect on platelet function

Laropiprant is an effective and selective antagonist of the PGD₂ (DP₁) receptor subtype 1. Laropiprant also has affinity for thromboxane A₂(TP) receptors, which is 190 times weaker than its affinity for DP₁ receptors.

The effect of laropiprant on platelet functions was studied in a series of studies. In therapeutic doses, Laropiprant did not have a clinically significant effect on platelet functions, including bleeding time and collagen-induced platelet aggregation. It has been demonstrated that Laropiprant did not reduce the antiplatelet effect of acetylsalicylic acid and did not affect bleeding time while taking acetylsalicylic acid.

Clinical studies

In groups of patients treated with the drug Tredaptive^® at a dose of 2000 mg/40 mg in combination with or without HMG-CoA reductase inhibitors compared with placebo, a significant reduction in LDL-C concentrations (-18.9%, -0.5% respectively), TG (-21.7%, 3.6% respectively), LDL-C:HDL-C ratio (-28.9%, 2.3% respectively), non-HDL-C (non-high-density lipoprotein cholesterol) (- 19.0%, 0.8% respectively), apo B ( -16.4%, 2.5% respectively), TC (-9.2%, -0.6% respectively), Lp(a) (-17.6%, 1.1% respectively) and TC:HDL-C ratio (-21.2 %, 1.9% respectively) and at the same time a significant increase in HDL-C (18.8% – 1.2% respectively), and apo A-I (11.2%, 4.3% respectively) relative to baseline values. In general, the therapeutic effect on all lipid profile parameters was consistent across all patient subgroups. Among patients treated with the drug Tredaptive^® or extended-release nicotinic acid, or placebo, and taking HMG-CoA reductase inhibitors (29% atorvastatin [5 – 80 mg], 54% simvastatin [10-80 mg], 17% other HMG-CoA reductase inhibitors [2.5-180 mg] (pravastatin, fluvastatin, rosuvastatin, lovastatin)) 9% additionally took ezetimibe [10 mg]. The effect on the lipid profile was the same, regardless of whether patients received monotherapy with the drug Tredaptive^® or in combination with HMG-CoA reductase inhibitors and/or with ezetimibe.

In a multicenter, double-blind, 12-week factorial study, the group of patients treated with the drug Tredaptive^® (1000 mg/20 mg) in combination with simvastatin was compared with groups of patients receiving simvastatin monotherapy and monotherapy with the drug Tredaptive^® (1000 mg/20 mg) for 4 weeks. A significant reduction in LDL-C concentrations (-44.2%, -37.4%, -8.2% respectively), TG (- 25.8%, -15.7%, -18.7% respectively), TC (- 27.9 %, – 25.8 %, – 4.9 % respectively) and a significant increase in HDL-C concentration (19.2%, 4.2%, 12.5% respectively) were shown. When comparing groups of patients taking the drug Tredaptive^®(2000 mg/40 mg) in combination with simvastatin with the group of patients receiving simvastatin monotherapy and monotherapy with the drug Tredaptive^® (2000 mg/40 mg) for 12 weeks, a significant reduction in LDL-C concentrations (-47.9%, – 37.0 %, -17.0 % respectively), TG (- 33.3 %, -14.7 %, – 21.6 % respectively), apo B ( – 41.0 %, – 28.8 %, – 17.1 % respectively) and TC (- 2.6 %, – 24.9 %, – 9.1 % respectively), as well as the ratios LDL-C : HDL-C (-57.1%, -39.8% -31.2% respectively) and TC: HDL-C (-43.0%, -28.0%, -24.9% respectively), non-HDL-C (-45.8%, -33.4%, -18.1% respectively), and a significant increase in HDL-C concentration (27.5 %, 6.0 %, 23.4 % respectively) were observed. Further analysis of the data showed that the use of the drug Tredaptive^® (2000 mg/40 mg) in combination with simvastatin compared with simvastatin monotherapy significantly increased the concentration of apo A-I (8.6 %, 2.3% respectively) and significantly reduced the concentration of Lp(a) (-19.8%, 0.0% respectively). A study of the efficacy and safety of the drug Tredaptive^® in combination with simvastatin in doses greater than 40 mg was not conducted.

Pharmacokinetics

Absorption

Nicotinic acid after simultaneous administration of nicotinic acid with food at a dose of 2 g as part of two Tredaptive^® tablets with extended release of nicotinic acid, the time to reach maximum plasma concentration (T_max) averaged 4 h, the mean value of the area under the concentration-time curve (AUC_0-∞) was 58.0 µmol/L×h, and the mean value of the maximum plasma concentration (C_max) was about 20.2 µmol/L. Bioavailability (with and without food) is at least 72%, based on the amount of nicotinic acid excreted by the kidneys. The bioavailability of nicotinic acid is not reduced when taken orally simultaneously with fatty food.

Laropiprant after simultaneous administration of laropiprant with food in an amount of 40 mg as part of two Tredaptive^® tablets, Laropiprant was rapidly absorbed and T_max averaged 1 h, the mean AUC_0-∞ value was approximately 13 µmol/L×h, and the mean C_max value was about 1.6 µmol/L. The rate and extent of absorption did not change when taken simultaneously with fatty food. The pharmacokinetics of laropiprant is linear, AUC and C_max values increase approximately proportionally to the dose increase. The mean absolute bioavailability of laropiprant was approximately 71% after taking two Tredaptive^® tablets (40 mg laropiprant) on an empty stomach.

Distribution

Nicotinic acid binds to plasma proteins less than 20% of the administered dose.

Laropiprant the mean volume of distribution at steady state after a single intravenous administration of 40 mg laropiprant to healthy volunteers was approximately 70 L. Laropiprant is almost completely (>99%) bound to plasma proteins, regardless of the plasma concentration value. Laropiprant crosses the placental barrier in rats and rabbits.

Metabolism

Nicotinic acid Nicotinic acid is metabolized by two pathways depending on the dose and rate of administration. The first pathway results in the formation of nicotinamide adenine dinucleotide (NAD) and nicotinamide. In humans, nicotinamide is further metabolized to N-methylnicotinamide (MNA) and N-4-methyl-2-pyridone-5-carboxamide (2PY). The second pathway results in the conjugation of glycine and nicotinic acid to form nicotinuric acid. When low doses of nicotinic acid are administered or the absorption rate is reduced, metabolism occurs predominantly via the first pathway. When high doses are administered or the absorption rate is high, as nicotinuric acid (the first metabolic pathway) becomes saturated, a larger amount of orally administered nicotinic acid enters the systemic circulation as nicotinic acid (i.e., unchanged). When nicotinic acid is administered in doses of 1-2 g, the increase in plasma concentration of nicotinuric acid is dose-dependent, and this indicates that the second metabolic pathway does not become saturated when the drug is taken in therapeutic doses.

Laropiprant Laropiprant is metabolized predominantly by acylglucuronidation and only a small part undergoes oxidation. The acylglucuronide is then excreted through the intestine (with bile) and kidneys. Laropiprant and its acylglucuronide are the main components circulating in the systemic bloodstream in humans.

The main component excreted in feces (73% of radioactivity) was Laropiprant (consisting of the unabsorbed laropiprant itself and/or its hydrolyzed glucuronic acid conjugate). In urine, Laropiprant was determined mainly as an acylglucuronide (64% of radioactivity) and only 5% of radioactivity was accounted for by unchanged Laropiprant. Oxidation of laropiprant occurs with the participation of the CYP3A4 isoenzyme, and several isoforms of uridine diphosphate glucuronosyltransferase (1A1, 1A3, 1A9 and 2B7) are involved in the glucuronidation process.

Excretion

Nicotinic acid Nicotinic acid is excreted primarily by the kidneys as metabolites.

Laropiprant Laropiprant is excreted primarily by acylglucuronidation followed by elimination of the glucuronide through the intestine (with bile) and kidneys. After oral administration of labeled ¹⁴C laropiprant, approximately 68% of the administered radioactivity was found in feces (mainly unchanged). Almost the entire administered dose was excreted within 96 hours. The half-life (T_1/2) after simultaneous administration with food of 40 mg laropiprant (as part of two Tredaptive^® tablets) was approximately 17 hours. Steady state was reached within 2 days with a single dosing regimen with signs of minimal accumulation (increase in AUC by approximately 1.3 times and C_max by approximately 1.1 times).

Children

Studies of the drug Tredaptive^® in children have not been conducted.

Elderly patients

Nicotinic acid pharmacokinetic data for elderly patients (over 65 years) are not available. In patients 18-65 years of age, age does not have a clinically significant effect on the pharmacokinetics of nicotinic acid in lipid-lowering doses. There are no changes in the oral bioavailability of nicotinic acid depending on age.

LaropiprantDose adjustment for elderly patients is not required. Age does not have a clinically significant effect on the pharmacokinetics of laropiprant.

Patients with hepatic impairment

A study of the drug Tredaptive^® in patients with impaired liver function has not been conducted.

Nicotinic acid (see section “Contraindications”).

Laropiprant since the drug is excreted primarily as metabolites, moderate hepatic impairment has a significant effect on the pharmacokinetics of laropiprant, increasing AUC and C_max values by approximately 2.8 and 2.2 times, respectively.

Patients with renal impairment

A study of the drug Tredaptive^® in patients with impaired renal function has not been conducted.

Nicotinic acid (see section “With caution”).

Laropiprant Compared with healthy volunteers, in patients with severe renal impairment (not undergoing hemodialysis), administration of laropiprant at a dose of 40 mg was not accompanied by clinically significant changes in AUC and C_max values. Accordingly, changes in pharmacokinetics are not expected in patients with mild to moderate renal impairment, but this does not apply to patients with end-stage chronic renal failure on hemodialysis.

Gender

Nicotinic acidDose adjustment for nicotinic acid based on gender is not required. Gender does not have a clinically significant effect on the pharmacokinetics of nicotinic acid. The bioavailability of orally administered nicotinic acid in lipid-lowering doses is the same in men and women. Women may have a slight increase in plasma concentrations of nicotinuric and nicotinic acid.

LaropiprantDose adjustment in men and women is not required. Gender does not have a clinically significant effect on the pharmacokinetics of laropiprant.

Race

Nicotinic acidDose adjustment for nicotinic acid based on race is not required. Race does not have a clinically significant effect on the pharmacokinetics of extended-release nicotinic acid (based on pharmacokinetic data for Caucasian and Black races, as well as individuals from South America and Native American populations). Caution should be exercised when prescribing Tredaptive^® concomitantly with simvastatin or simvastatin/ezetimibe (especially at a simvastatin dose of 40 mg and above) to patients of Chinese ethnicity.

LaropiprantDose adjustment for laropiprant based on race is not required. Race does not have a clinically significant effect on the pharmacokinetics of laropiprant (based on pharmacokinetic data for Caucasian, Mongoloid, and Black races, as well as individuals from South America and Native American populations).

Indications

• Treatment of dyslipidemia, especially in patients with mixed dyslipidemia (increased LDL cholesterol and triglycerides, decreased HDL cholesterol), primary hypercholesterolemia (heterozygous familial and non-familial).

The drug Tredaptive^® should be used in patients in combination with HMG-CoA reductase inhibitors when HMG-CoA reductase inhibitor monotherapy is ineffective. The drug can be used in monotherapy in patients only in case of intolerance to HMG-CoA reductase inhibitors. During treatment with Tredaptive^®, adherence to diet and the use of non-pharmacological treatment methods (for example, physical exercise, weight loss) should be continued.

ICD codes

Dosage Regimen

Orally, in the evening with food. Do not chew the tablets. The initial dose of the drug is one tablet once a day (1000 mg/20 mg). After 4 weeks, patients are recommended to switch to a maintenance dose – two tablets once a day (2000 mg/40 mg). Study of doses above 2000 mg/40 mg has not been conducted and use is not recommended. To reduce the manifestations of the main side effect “flushing” of the skin of the head, neck and upper body, alcohol, hot drinks and spicy foods should not be consumed while taking the drug.

If the patient has stopped taking Tredaptive^® for less than 7 days, treatment can be resumed at the usual dose. If the break exceeded 7 days, treatment should be resumed with the initial dose of one tablet (1000 mg/20 mg), and after a week you can switch back to the maintenance dose of two tablets (2000 mg/40 mg).

Patients switching from treatment with an extended-release nicotinic acid preparation at a dose of ≥ 2000 mg to treatment with Tredaptive^® can start taking Tredaptive^® with two tablets (2000 mg/40 mg). Patients switching from treatment with an extended-release nicotinic acid preparation at a dose of ≤2000 mg to treatment with Tredaptive^® should start taking Tredaptive^® with one tablet (1000 mg/20 mg). Patients switching from treatment with an immediate-release nicotinic acid preparation to treatment with Tredaptive^® should start taking Tredaptive^® with one tablet (1000 mg/20 mg), and then after 4 weeks switch to a maintenance dose – two tablets (2000 mg/40 mg).

Use in elderly patients

Dose adjustment in elderly patients is not required.

Use in children

Since the safety and efficacy of Tredaptive^® in children have not been studied, it is not recommended to prescribe the drug to children.

Use in patients with hepatic and renal impairment

A study of the use of Tredaptive^® in patients with hepatic and renal impairment has not been conducted. Like other drugs based on nicotinic acid, Tredaptive^® is contraindicated in patients with severe hepatic impairment, including of unclear etiology. Tredaptive^® should be prescribed with caution to patients with renal impairment, since Nicotinic acid and its metabolites are excreted primarily by the kidneys.

Combination therapy

Tredaptive^® can be combined with HMG-CoA reductase inhibitors to enhance the hypoglycemic effect. In clinical studies among 1072 patients receiving treatment with Tredaptive^®, extended-release nicotinic acid or placebo and receiving HMG-CoA reductase inhibitors (29% atorvastatin, 54% simvastatin, 17% other HMG-CoA reductase inhibitors (pravastatin, fluvastatin, rosuvastatin, lovastatin)) 9% also took ezetimibe.

Acetylsalicylic acid does not eliminate “flushing” of the skin of the HEAD, neck or upper body caused by taking nicotinic acid in lipid-lowering doses, so concomitant administration is not justified.

Since bile acid sequestrants reduce the bioavailability of nicotinic acid, Tredaptive^® should be taken no later than 1 hour before, and no earlier than 4 hours after taking drugs from the group of bile acid sequestrants.

Adverse Reactions

Tredaptive^® is generally well tolerated. Adverse reactions are usually mild and resolve quickly after discontinuation of the drug.

“Flushing” of the skin of the head, neck and upper body is the most common adverse reaction of Tredaptive^®. In four combined placebo-controlled and active-controlled studies (4747 patients), in 12.3% of patients out of 2548 taking Tredaptive^®, “flushing” was assessed as possibly, probably or related to drug intake. In these studies, the number of patients taking Tredaptive^®, nicotinic acid (extended-release) or placebo/simvastatin, and who discontinued due to the occurrence of “flushing” of the skin of the head, neck and upper body, accompanied by redness, feeling of heat, skin itching or tingling, was 7.2%, 16.6% and 0.4%, respectively. The number of patients who discontinued Tredaptive^® due to other specific adverse events was < 1%.

During treatment with Tredaptive^® for up to 1 year in combination with HMG-CoA reductase inhibitors or without them, in addition to “flushing” of the skin of the head, neck and upper body, patients experienced the following (possibly, probably and definitely related to the use of the drug) adverse reactions with a frequency of >1%

Gastrointestinal disorders diarrhea, dyspepsia, nausea, vomiting.

Nervous system disorders dizziness, headache, paresthesia.

Skin and subcutaneous tissue disorders erythema, itching, rash, urticaria.

General disorders and administration site conditions feeling hot.

Hypersensitivity reactions

A severe hypersensitivity reaction was observed with a frequency of < 1% and was characterized by multiple symptoms: angioedema, skin itching, erythema, paresthesia, loss of consciousness, urticaria, “flushing”, shortness of breath, nausea, involuntary urination and defecation, cold sweat, chills and trembling, increased blood pressure (BP), lip swelling, burning, skin rashes, arthralgia, peripheral edema of the lower extremities and tachycardia.

Laboratory parameters

Marked and persistent increase in transaminase activity was rarely observed. The frequency of clinically significant increases in serum transaminase activities (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)) more than 3 times the upper limit of normal was 1.0% in patients taking Tredaptive^® in combination with HMG-CoA reductase inhibitors or without. These deviations were usually not accompanied by any clinical symptoms, and after drug discontinuation, the indicators returned to normal on their own.

A clinically significant increase in creatine phosphokinase activity, exceeding the upper limit of normal by more than 10 times, was observed in 0.3% of patients receiving Tredaptive^® in combination with HMG-CoA reductase inhibitors or without. In addition to the indicated deviations in laboratory parameters, an increase in lactate dehydrogenase (LDH) activity, fasting glucose, uric acid, total bilirubin and amylase, and a decrease in serum phosphorus and platelet count were also observed.

Additional adverse reactions were registered during the use of Tredaptive^® or other nicotinic acid preparations (in combination with HMG-CoA reductase inhibitors or without them) or during clinical studies of Tredaptive^® with a frequency of < 1%

Infections and infestations rhinitis.

Immune system disorders anaphylactic shock, angioedema, type 1 hypersensitivity reactions.

Metabolism and nutrition disorders decreased glucose tolerance, exacerbation of gout.

Psychiatric disorders agitation, insomnia.

Nervous system disorders migraine, syncope.

Eye disorders macular cystic edema, toxic amblyopia.

Cardiac disorders atrial fibrillation and other types of arrhythmia, palpitations, tachycardia.

Vascular disorders marked decrease in BP, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders dyspnea.

Gastrointestinal disorders abdominal pain, oral mucosal edema, belching, peptic ulcer.

Hepatobiliary disorders jaundice.

Musculoskeletal and connective tissue disorders muscle weakness and pain.

Skin and subcutaneous tissue disorders acanthokeratoderma, dry skin, hyperpigmentation, macular rash, increased sweating (night and cold sweats), vesicular and vesiculobullous rash.

General disorders and administration site conditions asthenia, chills, facial edema, generalized edema, pain, peripheral edema.

Contraindications

• Hypersensitivity to any of the components of the drug;
• Severe hepatic impairment or liver disease of unclear origin;
• Active phase of peptic ulcer;
• Arterial bleeding;
• Children under 18 years of age;
• Pregnancy and breastfeeding period.

With caution

Caution should be exercised when prescribing to patients with a history of liver disease and/or excessive alcohol consumption. Caution should be exercised when co-administering with HMG-CoA reductase inhibitors in patients predisposed to the development of myotoxic complications or with a family history of muscle diseases (myotoxicity). For all patients with concomitant administration of Tredaptive^® with HMG-CoA reductase inhibitors, it is necessary to monitor for the appearance of symptoms of myopathy/rhabdomyolysis.

Caution should be exercised when prescribing to patients with impaired renal function; diabetes mellitus or risk of its development; unstable angina or in the acute phase of myocardial infarction, especially patients receiving nitrates, slow calcium channel blockers and α-blockers; patients with gout or predisposition to it (hyperuricemia); with concomitant administration with fibrates.

When using Tredaptive^®, prothrombin time does not increase, however, if surgical intervention is necessary, a thorough assessment of blood coagulation parameters is necessary.

Use in Pregnancy and Lactation

A study of the effect of Tredaptive^® on human reproductive function has not been conducted. It is unknown whether the use of the drug during pregnancy can harm the embryo or affect reproductive ability. Tredaptive^® should not be prescribed during pregnancy.

Nicotinic acid Nicotinic acid did not have a teratogenic effect when administered daily doses up to 300 mg/kg to rats and up to 300 mg/kg to rabbits (with an excess of 253 and 104 times, respectively, the AUC of extended-release nicotinic acid in humans when taking two tablets of Tredaptive^® per day). A slight decrease in the average weight gain of the female and fetal weight, incomplete ossification of the lumbosacral vertebrae, as well as cases of incomplete ossification of the cervical vertebra, sternum segment and hyoid bone in the fetus are observed when doses of 1000 mg/kg/day are administered to rats (with an excess of 959 times the AUC of extended-release nicotinic acid in humans when taking two tablets of Tredaptive^® per day). Similar changes were observed when doses of 900 mg/kg/day were administered to rabbits (with an excess of 629 times the AUC of extended-release nicotinic acid in humans when taking two tablets of Tredaptive^® per day).

Laropiprant Laropiprant did not have a teratogenic effect when administered daily doses up to 100 mg/kg to rats and 125 mg/kg to rabbits (with an excess of 153 and 438 times, respectively, the AUC of laropiprant in humans when taking two tablets of Tredaptive^® per day). A slight decrease in the average weight gain of the female and fetus, a slight increase in offspring mortality, as well as an increase in the frequency of an additional rib and cases of incomplete ossification of the sternum segment in the fetus were observed when doses of 400 mg/kg/day were administered to rats (with an excess of 513 times the AUC of laropiprant in humans when taking two tablets of Tredaptive^® per day). Tredaptive^® should not be prescribed during breastfeeding. A study of Tredaptive^® in lactating animals has not been conducted.

Nicotinic acid Nicotinic acid is excreted in breast milk.

Laropiprant data on the excretion of laropiprant in breast milk are not available. Excretion of laropiprant into the milk of rats has been established.

Use in Hepatic Impairment

Should be prescribed with caution to patients with liver diseases. Contraindicated in severe hepatic impairment or liver disease of unclear origin.

Use in Renal Impairment

Should be prescribed with caution to patients with impaired renal function.

Pediatric Use

Contraindicated in children under 18 years of age.

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

When prescribing Tredaptive^® in combination with HMG-CoA reductase inhibitors, it is necessary to read the instructions for medical use of these drugs.

Effect on the liver

Clinical features associated with the transition of treatment from immediate-release forms of nicotinic acid to treatment with Tredaptive^®, containing extended-release nicotinic acid, have not been studied. However, cases of severe hepatotoxicity up to fulminant liver necrosis are known when taking the same dose when switching from immediate-release forms to extended-release forms of nicotinic acid. Thus, when switching from treatment with immediate-release forms of nicotinic acid to treatment with Tredaptive^®, the initial dose of the drug should not exceed 1000 mg/20 mg.

Tredaptive^® should be prescribed with caution to patients who consume alcohol and/or patients with a history of liver disease. Severe liver dysfunction, including of unclear etiology, is a contraindication to treatment with Tredaptive^®.

As with treatment with other lipid-lowering drugs, treatment with nicotinic acid preparations may be accompanied by changes in liver function tests. In patients taking Tredaptive^® (2548 patients for 12-52 weeks, including treatment for 8-48 weeks with a dose of 2000 mg/40 mg), the frequency of increased ALT and/or AST activity, related to treatment (with a 3-fold excess of the upper limit of normal) was 1% and practically did not differ from the rates in the groups treated with extended-release forms of nicotinic acid, as well as placebo/simvastatin (0.5% and 0.9%, respectively). The increase in transaminase activity is reversible after discontinuation of Tredaptive^®.

It is recommended to assess liver function before starting treatment with Tredaptive^® and then every 6-12 weeks during the first year of treatment, and thereafter at least once every 6 months. If transaminase activity increases, regular monitoring is recommended until the values return to normal. In case of a persistent increase in “hepatic” transaminase activity (exceeding the upper limit of normal by 3 times), a dose reduction or discontinuation of the drug is recommended.

Effect on Skeletal Muscle.

Rare cases of myopathy (rhabdomyolysis) have been associated with the concurrent use of niacin in lipid-lowering doses (>1 g/day) and HMG-CoA reductase inhibitors. In 2548 patients treated with Tredaptive^® for 12-52 weeks (including 8 to 48 weeks with doses of 2000 mg/40 mg; combined treatment with HMG-CoA reductase inhibitors in 1601 patients), the frequency of increased creatine phosphokinase activity (more than 10 times the upper limit of normal) was 0.3%, and did not differ from the combined rate in the niacin and placebo/simvastatin treatment groups (0.2% and 0.2%, respectively). The frequency of myopathy and rhabdomyolysis during treatment with Tredaptive^® was comparable to the frequency with placebo or HMG-CoA reductase inhibitor treatment. When Tredaptive^® is co-administered with HMG-CoA reductase inhibitors, the potential benefits and risks should be carefully assessed, and patients should be closely monitored for symptoms such as hypersensitivity, weakness, and muscle pain, especially during the initial treatment period and after a dose increase of any of the drugs. If these symptoms occur, creatine phosphokinase concentration should be periodically determined, although this does not guarantee the prevention of severe myopathy.

During an interim analysis of an ongoing clinical study by an independent safety monitoring committee, an increased likelihood of myopathy was identified in patients of Chinese ethnicity taking Tredaptive^® concurrently with simvastatin at a dose of 40 mg. Therefore, additional precautions are necessary when prescribing Tredaptive^® concurrently with simvastatin or ezetimibe/simvastatin (especially at a simvastatin dose of 40 mg and above) to patients of Chinese ethnicity. Since the risk of myopathy depends on the dose of HMG-CoA reductase inhibitors, the use of Tredaptive^® concurrently with simvastatin at a dose of 80 mg or simvastatin/ezetimibe at a dose of 80/10 mg is not recommended for patients of Chinese ethnicity. The potential for an increased risk of myopathy with the use of Tredaptive^® concurrently with simvastatin or simvastatin/ezetimibe in other patients of Mongoloid race is unknown.

Impaired Renal Function

Since Nicotinic acid and its metabolites are primarily excreted by the kidneys, Tredaptive^® should be used with caution in patients with impaired renal function.

Effect on Plasma Glucose Concentration

It is known that taking niacin on an empty stomach is accompanied by an increase in plasma glucose concentration. In 798 patients by week 24 of treatment with Tredaptive^® or extended-release niacin on an empty stomach (541 patients), the mean increase in plasma glucose concentration was 4 mg/dL. The mean increase in glycated hemoglobin concentration in patients with diabetes mellitus was 0.2% and 0.1%, respectively, after treatment with Tredaptive^® (n=136) or extended-release niacin (n=78) (adjustment of hypoglycemic therapy was allowed). Patients with diabetes or at risk of developing it should be monitored, and diet and hypoglycemic therapy should be adjusted as necessary.

Acute Coronary Syndrome

As with other niacin-based drugs, Tredaptive^® should be used with caution in patients with unstable angina or in the acute phase of myocardial infarction, especially if patients are receiving nitrates, slow calcium channel blockers, and α-adrenergic blockers.

Effect on Blood Count

As with other niacin-based drugs, treatment with Tredaptive^® may be accompanied by a slight decrease in platelet count. According to a clinical study, by week 24 of treatment with Tredaptive^® at a dose of 2000 mg/40 mg, the mean decrease in platelet count was 14%. Treatment with Tredaptive^® was not associated with an increase in prothrombin time. However, if surgical intervention is necessary, a thorough assessment of blood coagulation parameters is required.

Effect on Uric Acid Concentration

As with other niacin-based drugs, treatment with Tredaptive^® may be accompanied by a slight increase in uric acid concentration. In patients by week 24 of treatment with Tredaptive^® at a dose of 2000 mg/40 mg, the mean increase in uric acid concentration was 14.7% of the baseline concentration. Therefore, Tredaptive^® should be used with caution in patients with gout or a predisposition to it.

Effect on Driving and Operating Machinery

No studies have been conducted to assess the effect on the ability to drive a car or operate machinery. Nevertheless, when driving and operating machinery, it should be remembered that dizziness may occur while taking Tredaptive^®.

Overdose

In case of an overdose of Tredaptive^®, symptomatic and supportive treatment is recommended. Cases of overdose have occurred. The maximum dose of Tredaptive^® was 5000 mg/100 mg (five tablets) without any consequences for the patients.

Nicotinic acid

In case of an overdose of niacin, supportive treatment is recommended.

Laropiprant

When laropiprant was taken as a single dose by healthy volunteers up to 900 mg and in multiple doses up to 450 mg/day for 10 days, the drug was generally well tolerated. Doses above 900 mg have not been studied in humans. During long-term use of laropiprant in daily doses of 300 mg and higher, patients experienced prolongation of collagen-induced platelet aggregation.

Drug Interactions

Interaction of Nicotinic Acid with Other Drugs

Antihypertensive Drugs Nicotinic acid may potentiate the effect of ganglion blockers and other vasoactive drugs, leading to postural hypotension.

HMG-CoA Reductase Inhibitors No clinically significant effect of Tredaptive^® on the pharmacokinetic parameters of simvastatin, on the AUC and C_max of simvastatin lactone, was noted. Only a slight increase in the AUC and C_max of simvastatin acid was observed.

Cytochrome P450 (CYP) Enzyme Systems According to in vitro studies, Nicotinic acid and its metabolites (nicotinuric acid, methylnicotinamide, and 1-methyl-2-pyridone-5-carboxamide) did not inhibit the isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4-mediated reactions, and estradiol-3-glucuronidation mediated by uridine diphosphate-glucuronosyltransferase A1.

Effect of Other Drugs on Nicotinic Acid.

Bile Acid Sequestrants Due to the reduction in the bioavailability of “acidic” drugs, including nicotinic acid, by bile acid sequestrants, Tredaptive^® should be taken no later than 1 hour before, and no earlier than 4 hours after taking drugs from the bile acid sequestrant group.

Dietary Supplements Containing Niacin The concurrent use of Tredaptive^® with vitamins and other dietary supplements containing large doses of niacin or nicotinamide has not been studied. When prescribing Tredaptive^®, the physician should take into account the dose of niacin the patient is already taking as part of vitamin preparations or dietary supplements.

Laboratory Test Data In urine glucose analysis, Nicotinic acid may cause a false-positive reaction with copper sulfate solution (Benedict’s reagent).

Effect of Laropiprant on Other Drugs

Midazolam The use of laropiprant (40 mg) did not affect the pharmacokinetics of midazolam, which is a substrate of the CYP3A4 isoenzyme. Thus, Laropiprant is not an inhibitor or inducer of the CYP3A4 isoenzyme. Although Laropiprant did not affect the parameters of midazolam, the plasma concentration of its main metabolite, 1-hydroxymidazolam, approximately doubled after multiple doses of laropiprant. Since 1-hydroxymidazolam is an active metabolite, enhanced pharmacodynamic activity of midazolam cannot be excluded, and therefore, caution should be exercised when these drugs are co-administered.

Other Drugs 1-hydroxymidazolam is metabolized primarily by uridine diphosphate-glucuronosyltransferases (UGT) 2B4 and 2B7. Results from clinical and in vitro studies indicate that Laropiprant is a moderate inhibitor of UGT2B4/UGT2B7 enzymes. These enzymes are involved in the metabolism of a limited number of drugs. Although Laropiprant increases the concentration of these drugs by no more than 2 times, caution should be exercised when Tredaptive^® is co-administered with drugs metabolized by UGT2B4 or UGT2B7 enzymes (e.g., with azidothymidine).

Laropiprant did not have a clinically significant effect on the pharmacokinetic parameters of the following drugs: simvastatin, warfarin, oral contraceptives, rosiglitazone, and digoxin. Thus, no drug interactions of laropiprant with substrates of cytochrome P450 isoenzymes 3A4, 2C9, 2C8, and P-glycoprotein are expected. In in vitro studies, Laropiprant did not inhibit reactions mediated by the isoenzymes CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP2E1.

Clopidogrel No significant effect of laropiprant on clopidogrel-induced suppression of ADP-induced platelet aggregation was observed, but a slight suppression of clopidogrel on collagen-induced platelet aggregation was noted. The clinical significance of these phenomena has not been established.

Acetylsalicylic Acid as an Antiplatelet Agent In a clinical study, concurrent administration of laropiprant and acetylsalicylic acid did not have any effect on collagen-induced platelet aggregation or on bleeding time compared to taking acetylsalicylic acid alone.

Acetylsalicylic Acid and Clopidogrel In a clinical study of patients with dyslipidemia taking acetylsalicylic acid and clopidogrel concurrently, Laropiprant caused transient (for up to 4 hours after dose administration) suppression of platelet function in vivo (assessed by bleeding time and platelet aggregation studies). Patients receiving Tredaptive^® concurrently with acetylsalicylic acid and clopidogrel should be regularly monitored.

Effect of Other Drugs on Laropiprant

CYP3A4 Isoenzyme Inhibitors Clarithromycin (a potent inhibitor of cytochrome CYP3A4 isoenzyme) did not have a clinically significant effect on the pharmacokinetics of laropiprant. Thus, no clinically significant effect of other CYP3A4 isoenzyme inhibitors on the pharmacokinetic parameters of laropiprant is expected.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.