Torvazin^® Plus (Capsules) Instructions for Use

Marketing Authorization Holder

Egis Pharmaceuticals PLC (Hungary)

Contact Information

EGIS Pharmaceutical Plant CJSC (Hungary)

ATC Code

C10BA05 (Atorvastatin and Ezetimibe)

Active Substances

Ezetimibe (Rec.INN registered by WHO)

Atorvastatin (Rec.INN registered by WHO)

Dosage Forms

	Torvazin® Plus	Capsules 10 mg+10 mg: 30 or 90 pcs.
		Capsules 20 mg+10 mg: 30 or 90 pcs.
		Capsules 40 mg+10 mg: 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size 0, unmarked, with a yellow body and a light brown cap, containing spherical pellets white or almost white, odorless or almost odorless and a round, flat tablet white or almost white, with a bevel, with an engraved stylized letter E on one side of the tablet and the number 612 on the other side of the tablet, odorless or almost odorless.

Excipients: calcium carbonate, hypromellose, polysorbate 80, croscarmellose sodium, sugar spheres (sucrose (13 mg) 62.5-91.5%, corn starch 8.5-37.5%), talc, mannitol, microcrystalline cellulose, low-substituted hypromellose, povidone K25, sodium lauryl sulfate, magnesium stearate.

Body composition titanium dioxide (E171), iron oxide yellow (E172), gelatin.
Cap composition titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172), gelatin.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Capsules hard gelatin, size 0, unmarked, with a yellow body and a reddish-brown cap, containing spherical pellets white or almost white, odorless or almost odorless and a round, flat tablet white or almost white, with a bevel, with an engraved stylized letter E on one side of the tablet and the number 612 on the other side of the tablet, odorless or almost odorless.

Excipients: calcium carbonate, hypromellose, polysorbate 80, croscarmellose sodium, sugar spheres (sucrose (26 mg) 62.5-91.5%, corn starch 8.5-37.5%), talc, mannitol, microcrystalline cellulose, low-substituted hypromellose, povidone K25, sodium lauryl sulfate, magnesium stearate.

Body composition titanium dioxide (E171), iron oxide yellow (E172), gelatin.
Cap composition titanium dioxide (E171), iron oxide red (E172), gelatin.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Capsules hard gelatin, size 0, unmarked, with a yellow body and a dark brown cap, containing spherical pellets white or almost white, odorless or almost odorless and a round, flat tablet white or almost white, with a bevel, with an engraved stylized letter E on one side of the tablet and the number 612 on the other side of the tablet, odorless or almost odorless.

Excipients: calcium carbonate, hypromellose, polysorbate 80, croscarmellose sodium, sugar spheres (sucrose (51.5 mg) 62.5-91.5%, corn starch 8.5-37.5%), talc, mannitol, microcrystalline cellulose, low-substituted hypromellose, povidone K25, sodium lauryl sulfate, magnesium stearate.

Body composition titanium dioxide (E171), iron oxide yellow (E172), gelatin.
Cap composition titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), iron oxide black (E172), gelatin.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (9) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; hypolipidemic agents in combinations; combinations of various hypolipidemic agents

Pharmacological Action

Mechanism of action, pharmacodynamic effects

The drug Torvazin^® Plus is a hypolipidemic agent that selectively reduces the absorption of cholesterol and some plant sterols in the intestine and also suppresses endogenous cholesterol synthesis.

Cholesterol enters the blood plasma as a result of intestinal absorption and endogenous synthesis. The drug Torvazin^® Plus contains Ezetimibe and Atorvastatin, two hypolipidemic components that complement each other in their mechanism of action. The combination of Atorvastatin + Ezetimibe reduces elevated plasma concentrations of total cholesterol, LDL-C, apolipoprotein B, triglycerides, and non-HDL cholesterol, calculated as the difference between total cholesterol concentration and HDL-C concentration, and increases the plasma concentration of HDL-C through dual inhibition of both cholesterol absorption and synthesis.

Atorvastatin

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor of steroids, including cholesterol. In the liver, triglycerides and cholesterol are incorporated into very low-density lipoproteins and released into the plasma for transport to peripheral tissues. Low-density lipoproteins are formed from VLDL and are catabolized primarily via the high-affinity LDL receptor.

Atorvastatin reduces plasma cholesterol concentrations and serum lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface, leading to enhanced uptake and catabolism of LDL.

Atorvastatin reduces LDL formation and the number of LDL particles. Atorvastatin leads to a pronounced and sustained increase in LDL receptor activity combined with a favorable change in the quality of circulating LDL particles. Atorvastatin effectively reduces LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually do not respond to hypocholesterolemic drugs.

Atorvastatin reduces levels of total cholesterol (30-46%), LDL-C (41-61%), Apo B (34-50%) and triglycerides (14-33%), while HDL-C and apolipoprotein A-I levels variably increase. These results are sustained in patients with heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus.

Reduction of total cholesterol, LDL-C and Apo B levels has been proven to be necessary to reduce the risk of cardiovascular complications and mortality associated with cardiovascular diseases.

Ezetimibe

Ezetimibe inhibits cholesterol absorption in the intestine and is effective when taken orally. The mechanism of action of ezetimibe differs from that of other classes of hypolipidemic agents. The molecular target of ezetimibe is the transport protein responsible for the intestinal absorption of cholesterol and phytosterols.

Ezetimibe is localized in the brush border of the small intestine and inhibits cholesterol absorption, leading to a decrease in the delivery of cholesterol from the intestine to the liver, while statins reduce cholesterol synthesis in the liver. These different mechanisms complement each other, leading to a decrease in plasma cholesterol concentration. In a 2-week clinical study involving 18 patients with hypercholesterolemia, Ezetimibe reduced intestinal cholesterol absorption by 54% compared with placebo.

A series of preclinical studies were conducted to determine the selectivity of ezetimibe for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [¹⁴C]-cholesterol and had no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Children

The European Medicines Agency has issued a waiver for the submission of clinical study results for the Atorvastatin + Ezetimibe combination in all pediatric age subgroups for the treatment of elevated cholesterol concentrations.

Preclinical safety data

Torvazin^® Plus

In studies with co-administration of ezetimibe and statins, the observed toxic effects were consistent with those typically associated with statin administration. Some toxic effects were more pronounced compared to statin administration alone, which is associated with pharmacokinetic and pharmacodynamic interactions when using both drugs. No such interactions were identified in clinical studies. Myopathies developed in rats only when exposed to doses several times higher than the therapeutic dose in humans.

Ezetimibe, either as monotherapy or in combination with statins, did not show potential genotoxicity in a series of in vivo and in vitro tests. Ezetimibe did not show carcinogenic effects in long-term studies.

Concomitant administration of ezetimibe and statins did not have a teratogenic effect in rabbits. A small number of skeletal deformities were noted in the offspring of pregnant rabbits.

Atorvastatin

Atorvastatin did not demonstrate mutagenic or clastogenic potential in a battery of 4 in vitro and 1 in vivo assays. Atorvastatin did not demonstrate carcinogenic effects in rats; however, when used in mice at high doses, the development of hepatocellular adenomas in males and hepatocellular carcinomas in females was noted.

Experimental animal studies have proven that HMG-CoA reductase inhibitors can affect the development of embryos or fetuses. In rats, rabbits and dogs, Atorvastatin did not affect fertility and did not have a teratogenic effect; however, when used in doses that were toxic to the mother, fetal toxicity was observed in rats and rabbits. Delayed development of rat offspring and reduced postnatal survival were noted with exposure to high doses of atorvastatin in pregnant females. There is evidence of placental passage in rats.

The concentration of atorvastatin in rat plasma is similar to that in milk. It is not known whether Atorvastatin or its metabolites are excreted in human breast milk.

Ezetimibe

Animal toxicity studies with long-term use did not reveal target organs of ezetimibe toxicity; the concentration of cholesterol in bile increased by 2.5-3.5 times. However, in a study in dogs that received ezetimibe doses up to 300 mg/kg/day for 1 year, no increase in the frequency of cholestasis or other changes in the liver and biliary tract was observed. The significance of these data for humans is unknown. It cannot be ruled out that the therapeutic use of ezetimibe is associated with the risk of developing cholelithiasis.

No carcinogenic potential was found for ezetimibe in long-term studies.

Ezetimibe did not affect the fertility of male and female rats, did not lead to the development of teratogenicity in rats and rabbits, and did not affect pre- and postnatal development. Ezetimibe crossed the placenta in pregnant rats and rabbits with repeated administration of doses equal to 1000 mg/kg/day. Concomitant administration of ezetimibe and lovastatin led to embryonic death.

Pharmacokinetics

The drug Torvazin^® Plus is bioequivalent to the combination of ezetimibe and atorvastatin.

Absorption

Atorvastatin

Atorvastatin is rapidly absorbed after oral administration, C_max is reached within 1-2 hours. The extent of absorption increases in proportion to the atorvastatin dose. After oral administration, atorvastatin film-coated tablets have a bioavailability of 95 to 99% compared to an oral solution. The absolute bioavailability of atorvastatin is about 12%, and the systemic availability of HMG-CoA reductase inhibitory activity is about 30%. The low systemic bioavailability is due to presystemic clearance in the gastrointestinal mucosa and/or first-pass metabolism in the liver.

Ezetimibe

After oral administration, Ezetimibe is rapidly absorbed and extensively metabolized in the small intestine and liver by conjugation to a pharmacologically active phenolic glucuronide. C_max of ezetimibe-glucuronide is observed within 1-2 hours, and of ezetimibe within 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined because the substance is practically insoluble in any of the aqueous solvents used for injection solutions.

Food intake did not affect the bioavailability of ezetimibe when taken orally as 10 mg tablets.

Distribution

Atorvastatin

The mean volume of distribution of atorvastatin is about 381 L. Atorvastatin is ≥98% bound to plasma proteins.

Ezetimibe

Ezetimibe and ezetimibe-glucuronide are bound to plasma proteins by 99.7% and 88-92%, respectively.

Metabolism

Atorvastatin

Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives, as well as various beta-oxidation products. Among other metabolic pathways, these products are further metabolized by glucuronidation. In vitro inhibition of HMG-CoA reductase by the ortho- and parahydroxylated metabolites is similar to that for atorvastatin. Approximately 70% of the circulating HMG-CoA reductase inhibitory activity is attributable to active metabolites.

Ezetimibe

Ezetimibe metabolism occurs mainly in the small intestine and liver by conjugation with glucuronide followed by biliary excretion. Ezetimibe undergoes minimal oxidative metabolism. The concentrations of ezetimibe and ezetimibe-glucuronide account for 10-20% and 80-90%, respectively, of the total ezetimibe concentration in plasma. Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma via enterohepatic recirculation. The T_1/2 for ezetimibe and ezetimibe-glucuronide is approximately 22 hours.

Excretion

Atorvastatin

After hepatic and/or extrahepatic metabolism, Atorvastatin is primarily excreted in the bile. However, Atorvastatin does not undergo significant enterohepatic recirculation. The mean plasma T_1/2 of atorvastatin in humans is about 14 hours. The half-life of inhibitory activity against HMG-CoA reductase is about 20-30 hours due to the action of active metabolites.

Atorvastatin is a substrate for the hepatic transporter enzymes OATP1B1 and OATP1B3. Atorvastatin metabolites are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporters MDR1 and BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Ezetimibe

After oral administration of 20 mg of ¹⁴C-labeled ezetimibe, 93% of the total ezetimibe was found in plasma relative to the total level of radioactive products. Within 10 days, approximately 78% of the administered radioactive products were excreted through the intestine with bile, 11% through the kidneys. After 48 hours, no radioactive products were detected in the plasma.

Pharmacokinetics in special patient groups

Elderly

Atorvastatin

The plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults, while the effect on lipids was comparable to that in the young patient population.

Ezetimibe

In elderly patients, the plasma concentration of total ezetimibe is approximately 2 times higher than in younger patients. The degree of LDL-C reduction and the safety profile were comparable in elderly and younger patients taking Ezetimibe.

Hepatic impairment

Atorvastatin

Plasma concentrations of atorvastatin and its active metabolites were significantly increased in patients with chronic alcoholic liver disease.

Ezetimibe

After a single 10 mg dose of ezetimibe, the mean AUC of total ezetimibe was 1.7 times greater in patients with mild hepatic impairment than in healthy volunteers. In a 14-day study of ezetimibe 10 mg/day in patients with moderate hepatic impairment, the mean AUC of total ezetimibe increased 4-fold on day 1 and day 14 compared with healthy volunteers. For patients with mild hepatic impairment, no dose adjustment of the drug is required. Since the consequences of an increase in the AUC of total ezetimibe are unknown, Ezetimibe is not recommended for patients with moderate and severe hepatic impairment.

Renal impairment

Atorvastatin

Renal disease does not affect the plasma concentrations of atorvastatin and its active metabolites or the lipid effects.

Ezetimibe

After a single oral dose of ezetimibe 10 mg in patients with chronic kidney disease stages 3-4, the AUC of total ezetimibe increased approximately 1.5-fold compared with healthy volunteers. In a patient after kidney transplantation receiving complex therapy, including cyclosporine, the AUC of total ezetimibe increased 12-fold.

Gender

Atorvastatin

The concentrations of atorvastatin and its active metabolites in women differ from those in men. There were no clinically significant differences in the effect on lipids between men and women.

Ezetimibe

The plasma concentration of total ezetimibe is slightly higher in women (by less than 20%) than in men. The degree of LDL-C reduction and the safety profile are comparable in men and women taking Ezetimibe.

SLCO1B1 Polymorphism

Atorvastatin

The hepatic uptake of all HMG-CoA reductase inhibitors, including atorvastatin, involves the OATP1B1 transporter protein. In patients with SLCO1B1 polymorphism, there is a risk of increased atorvastatin exposure, which may lead to an increased risk of rhabdomyolysis. The polymorphism of the gene encoding the OATP1B1 protein (SLCO1B1 c.521CC) is associated with a 2.4-fold increase in the AUC of atorvastatin compared to the corresponding value in individuals without this genotype (c.521TT). In such patients, a genetically determined impairment of the hepatic uptake process of atorvastatin is also possible. The possible impact on efficacy is unknown.

Indications

• For primary hypercholesterolemia as an adjunct to diet in adult patients who are indicated for therapy with single-component drugs in equivalent therapeutic doses.

ICD codes

Dosage Regimen

The drug is taken orally, at any time of the day, regardless of meals.

The recommended dose is 1 capsule once daily.

Before starting therapy with Torvazin^® Plus, patients should switch to a hypocholesterolemic diet and adhere to it throughout the entire course of treatment.

Torvazin^® Plus is not used for initial therapy.

Treatment or dose titration, if necessary, begins after the doses of the individual components included in the drug have been individually selected. After selecting the doses of each of the two single components, they switch to treatment with the combined drug in the corresponding selected dose.

Concomitant use with bile acid sequestrants

Torvazin^® Plus should be taken at least 2 hours before or 4 hours after taking bile acid sequestrants.

Concomitant use with other drugs

When Torvazin^® Plus is used concomitantly with the combination of elbasvir + grazoprevir, used for the treatment of hepatitis C, or with letermovir for the treatment of cytomegalovirus infection, the dose of atorvastatin should not exceed 20 mg/day (see sections “Special Precautions” and “Drug Interactions”).

The use of atorvastatin is not recommended in patients concomitantly taking letermovir with cyclosporine.

Special patient groups

Elderly patients

No dose adjustment is required for elderly patients (see section “Pharmacokinetics”).

Patients with impaired liver function

Torvazin^® Plus should be used with caution in patients with impaired liver function.

Torvazin^® Plus is contraindicated in patients with active liver disease (see section “Contraindications”).

Patients with impaired renal function

No dose adjustment is required for patients with impaired renal function (see section “Pharmacokinetics”).

Children

The safety and efficacy of Torvazin^® Plus in children and adolescents under 18 years of age have not been established due to the lack of clinical data (see section “Pharmacological Properties”).

Adverse Reactions

Tabulated summary of adverse reactions

Possible adverse reactions during the use of Torvazin^® Plus are distributed by system-organ class with an indication of their frequency of occurrence: common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000) and frequency unknown (cannot be estimated from the available data).

¹Adverse reactions associated with atorvastatin use.

²Adverse reactions associated with ezetimibe monotherapy.

³Adverse reactions associated with the combined use of ezetimibe and statins.

⁴Adverse reactions identified during post-marketing use of ezetimibe in combination with statins and in monotherapy.

The following adverse reactions have been reported with the use of some statins

• Sexual dysfunction, gynecomastia;
• Very rare cases of interstitial lung disease, especially with long-term therapy (see section “Special Precautions”);
• Diabetes mellitus, the frequency of development depends on the presence and/or absence of risk factors (fasting glucose concentration ≥ 5.6 mmol/L, BMI >30 kg/m², elevated TG levels, history of hypertension).

Contraindications

• Hypersensitivity to atorvastatin and ezetimibe or to any of the excipients included in the drug;
• Active liver disease or persistent elevation of serum hepatic transaminase activity, more than 3 times the upper limit of normal (ULN);
• Pregnancy;
• Breastfeeding period;
• Lack of reliable contraceptive methods in women of childbearing potential (see section “Use in Pregnancy and Lactation”);
• Concomitant use with the combination of glecaprevir + pibrentasvir, used for the treatment of hepatitis C;
• Concomitant use with the combination of elbasvir + grazoprevir.

Use in Pregnancy and Lactation

Women of childbearing potential

Women of childbearing potential should use reliable contraceptive methods during therapy (see section “Contraindications”).

Pregnancy

Torvazin^® Plus is contraindicated during pregnancy (see section “Contraindications”). There is no experience with the use of Torvazin^® Plus during pregnancy.

Atorvastatin

The safety of atorvastatin use in pregnant women has not been established. Controlled clinical studies of atorvastatin in pregnant women have not been conducted. There are rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. Animal studies have demonstrated reproductive toxicity (see subsection “Preclinical Safety Data”).

Ezetimibe

Clinical data on the use of ezetimibe during pregnancy are not available.

Breastfeeding period

Torvazin^® Plus is contraindicated during breastfeeding (see section “Contraindications”).

Due to the possibility of serious adverse reactions in the child, women taking Torvazin^® Plus should discontinue breastfeeding. In rats, the concentration of atorvastatin and its active metabolites in plasma is similar to that in milk. Animal studies have shown that Ezetimibe was detected in the milk of rats. There are no data on the excretion of atorvastatin and ezetimibe in human breast milk.

Fertility

Studies on the effect of Torvazin^® Plus on fertility have not been conducted.

Atorvastatin

In studies, Atorvastatin did not affect the fertility of the test animals.

Ezetimibe

Ezetimibe does not affect the fertility of male and female rats.

Use in Hepatic Impairment

Torvazin^® Plus should be used with caution in patients with impaired liver function. Torvazin^® Plus is contraindicated in patients with active liver disease.

Use in Renal Impairment

No dose adjustment is required for patients with impaired renal function (see section “Pharmacokinetics”).

Pediatric Use

The safety and efficacy of Torvazin^® Plus in children and adolescents under 18 years of age have not been established due to the lack of clinical data (see section “Pharmacological Properties”).

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

Myopathy/rhabdomyolysis

Torvazin^® Plus contains Atorvastatin. Atorvastatin, like other inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), can affect skeletal muscle and cause the development of myalgia, myopathy, and in rare cases, rhabdomyolysis – a syndrome manifested by an increase in CPK activity (more than 10 times the ULN), the development of myoglobinemia and myoglobinuria, subsequently leading to acute renal failure.

Cases of myopathy and rhabdomyolysis have been reported during the post-marketing use of ezetimibe. Most patients who developed rhabdomyolysis were taking statins concomitantly with ezetimibe. However, very rarely, the development of rhabdomyolysis has been reported with ezetimibe monotherapy and with its concomitant use with drugs that increase the risk of rhabdomyolysis.

Before starting treatment

Torvazin^® Plus should be prescribed with caution to patients with factors predisposing to the development of rhabdomyolysis. CPK activity should be monitored in the following cases before starting therapy

• Impaired renal function;
• Hypothyroidism;
• Personal or family history of hereditary muscle disorders;
• Previous toxic effects of HMG-CoA reductase inhibitors (statins) or fibrates on muscle tissue;
• History of liver disease and/or patients who consume significant amounts of alcohol;
• In patients over 70 years of age, the need for CPK control should be assessed, given that these patients already have factors predisposing to the development of rhabdomyolysis;
• Situations in which an increase in the plasma concentration of atorvastatin or ezetimibe is expected, such as interactions with other drugs (see section “Drug Interactions”) and special patient populations, including genetic subpopulations.

In such situations, the risk/benefit ratio should be assessed and medical monitoring of the patient’s condition should be carried out.

In case of a significant increase in CPK activity (>5 times ULN), the use of the drug should not be started.

Determination of CPK activity

CPK activity should not be measured after intense physical exertion or in the presence of a possible alternative cause for increased CPK activity that may distort the interpretation of the result. If baseline CPK levels are significantly elevated (5 times ULN), a control test should be performed after 5-7 days.

During treatment

• A doctor should be consulted immediately if muscle pain, muscle weakness, or cramps occur unexpectedly, especially in combination with malaise and fever.
• If these conditions occur, CPK activity should be determined. Therapy should be discontinued if CPK activity is significantly increased (>5 times ULN).
• If muscle symptoms are severe and cause daily discomfort (even if CPK is increased less than 5 times ULN), the advisability of discontinuing therapy should be considered.
• If symptoms disappear and CPK activity returns to normal, consideration should be given to re-prescribing atorvastatin or other HMG-CoA reductase inhibitors at lower doses with careful monitoring of the patient’s condition.
• In case of a significant increase in CPK activity (10 times ULN), suspected rhabdomyolysis, or diagnosed rhabdomyolysis, treatment with Torvazin^® Plus should be discontinued.
• Very rare cases of immune-mediated necrotizing myopathy with clinical manifestations of persistent proximal muscle weakness and increased serum CPK during treatment or after taking statins have been noted.

Since Torvazin^® Plus contains Atorvastatin, the risk of rhabdomyolysis increases with the concomitant use of drugs that increase the systemic concentration of atorvastatin, such as CYP3A4 inhibitors or transporter proteins (cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir, etc.). The risk of myopathy also increases with concomitant use with gemfibrozil and other fibrates, antiviral drugs for the treatment of hepatitis C (boceprevir, telaprevir, elbasvir + grazoprevir), erythromycin, nicotinic acid, or ezetimibe. If possible, drugs that do not interact with the components of Torvazin^® Plus should be used (see section “Adverse Reactions”).

If combination therapy is necessary, the expected benefit and possible risk of use should be carefully assessed. If it is necessary to use drugs that increase the systemic concentration of atorvastatin, it is recommended to use lower maximum doses of Torvazin^® Plus. In addition, when used concomitantly with potent CYP3A4 inhibitors, a lower initial dose of atorvastatin is recommended and periodic monitoring of patients’ condition should be carried out (see section “Drug Interactions”).

Atorvastatin should not be administered concomitantly with systemic fusidic acid preparations or within 7 days after stopping fusidic acid treatment. In patients for whom the use of systemic fusidic acid is considered necessary, statin treatment should be discontinued throughout the entire treatment with fusidic acid. Cases of rhabdomyolysis (including isolated cases with fatal outcome) have been reported in patients receiving the combination of fusidic acid and statins (see section “Drug Interactions”). The patient should consult a doctor immediately if symptoms such as muscle weakness, myalgia, or muscle tenderness on palpation occur.

Statin therapy can be resumed 7 days after taking the last dose of fusidic acid. In exceptional cases where prolonged systemic use of fusidic acid is required, for example, for the treatment of severe infections, the need for using Torvazin^® Plus and fusidic acid should be considered on a case-by-case basis and under careful medical supervision.

Liver Enzymes

In controlled clinical studies using the combination of ezetimibe and a statin, a consistent increase in liver transaminase activity (≥3 times the ULN) was observed (see section “Adverse Reactions”).

Liver function tests should be performed before starting treatment and periodically during further treatment. Patients who develop any signs or symptoms suggestive of liver injury should have liver function tests performed. In patients with elevated transaminase levels, monitoring should be continued until these abnormalities normalize. If the transaminase level is more than 3 times the ULN, a dose reduction or discontinuation of Torvazin^® Plus is recommended.

Torvazin^® Plus should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease.

Hepatic Insufficiency

The use of Torvazin^® Plus in patients with moderate or severe hepatic impairment is not recommended due to the lack of sufficient clinical data on the effect of increased ezetimibe exposure in this patient group (see section “Pharmacokinetics”).

Fibrates

The efficacy and safety of using ezetimibe concomitantly with fibrates (except fenofibrate) have not been sufficiently studied. If gallstone disease is suspected in patients receiving Ezetimibe or fenofibrate, a gallbladder examination should be performed, and therapy should be discontinued (see sections “Drug Interactions” and “Adverse Reactions”).

Cyclosporine

Initiation of Torvazin^® Plus therapy should be done with caution in patients taking cyclosporine. Cyclosporine concentrations should be monitored in patients concomitantly using Torvazin^® Plus with cyclosporine (see section “Drug Interactions”).

Anticoagulants

When Torvazin^® Plus is used concomitantly with warfarin (or another coumarin anticoagulant) or fluindione, regular INR monitoring should be performed (see section “Drug Interactions”).

Interstitial Lung Disease

Isolated cases of interstitial lung disease have been reported with the use of some statins, especially over a long period, which may present as dyspnea, non-productive cough, and deterioration in general health (weakness, weight loss, and fever) (see section “Adverse Reactions”). If interstitial lung disease is suspected, statin therapy should be discontinued.

Diabetes Mellitus

Some evidence suggests that statins, as a class, can cause an increase in blood plasma glucose concentrations, and in some patients at high risk of developing diabetes mellitus, a state of hyperglycemia requiring correction, as in diabetes mellitus, may develop. However, this risk does not outweigh the benefit of statin therapy in terms of vascular risks, so it should not be a reason for discontinuing therapy. Patients at risk (fasting blood glucose from 5.6 to 6.9 mmol/L, BMI >30 kg/m², elevated plasma TG levels, arterial hypertension) should be under medical supervision, including monitoring of blood biochemical parameters, in accordance with local guidelines.

Excipients

The drug contains sucrose (a component of sugar spheres). Torvazin^® Plus, 10 mg+10 mg, capsules contain 13 mg of sucrose, Torvazin^® Plus, 20 mg+10 mg, capsules contain 26 mg of sucrose, and Torvazin^® Plus, 40 mg+10 mg, capsules contain 51.5 mg of sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

Effect on Ability to Drive and Use Machines

Torvazin^® Plus has little to no effect on the ability to drive and use machines. However, considering the possibility of dizziness, caution should be exercised when driving vehicles and operating machinery.

Overdose

Torvazin^® Plus

In case of an overdose with Torvazin^® Plus, symptomatic and supportive treatment is indicated. Liver function tests and serum CK activity should be monitored.

Atorvastatin

Due to significant binding of atorvastatin to plasma proteins, it is unlikely that hemodialysis will significantly increase the elimination/clearance of atorvastatin.

Ezetimibe

In clinical studies investigating the efficacy and safety of ezetimibe at a dose of 50 mg/day in 15 healthy volunteers for 14 days or at a dose of 40 mg/day in 18 patients with primary hypercholesterolemia for 56 days, the drug was well tolerated.

Several cases of ezetimibe overdose have been reported, most of which were not accompanied by adverse reactions, and when they occurred, the adverse reactions were not serious. No toxicity was observed in animals after a single oral administration of ezetimibe (5000 mg/kg in rats and mice and 3000 mg/kg in dogs).

Drug Interactions

Pharmacodynamic Interaction

Atorvastatin, which is part of Torvazin^® Plus, is metabolized by the CYP3A4 isoenzyme and is a substrate for the liver transporter enzymes 1B1 (OATP1B1) and 1B3 (OATP1B3), involved in the uptake of statins by hepatocytes. Atorvastatin metabolites are substrates for the OATP1B1 transport protein. Atorvastatin is also identified as a substrate for P-glycoprotein (MDR1) and the Breast Cancer Resistance Protein (BCRP), which may limit the intestinal absorption and biliary clearance of atorvastatin (see section “Pharmacokinetics”).

Concomitant use of atorvastatin with inhibitors of the CYP3A4 isoenzyme or transport proteins may lead to an increase in the plasma concentration of atorvastatin and an increased risk of myopathy. An increased risk may also occur with the concomitant use of atorvastatin with other drugs that can cause myopathy, for example, with fibrates and ezetimibe (see section “Special Instructions”).

Pharmacokinetic Interaction

No clinically significant pharmacokinetic interaction was observed with the concomitant use of ezetimibe and atorvastatin.

Effect of Other Drugs on the Pharmacokinetics of Torvazin^® Plus

Atorvastatin

CYP3A4 Isoenzyme Inhibitors

Potent CYP3A4 inhibitors significantly increase atorvastatin plasma concentrations (see Table 1 and specific information below). Concomitant use of potent CYP3A4 inhibitors (e.g., cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, Hepatitis C virus products (e.g., elbasvir/grazoprevir) and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if possible. In cases where concomitant use of these drugs with atorvastatin cannot be avoided, appropriate clinical monitoring of the patient’s condition should be carried out (see Table 1).

Moderate CYP3A4 inhibitors (e.g., erythromycin, diltiazem, verapamil, and fluconazole) may increase the plasma concentration of atorvastatin (see Table 1). An increased risk of myopathy is observed with the use of erythromycin in combination with statins. Interaction studies assessing the effect of amiodarone or verapamil on Atorvastatin have not been conducted. Amiodarone and verapamil inhibit CYP3A4 activity, and their concomitant use with atorvastatin may lead to increased systemic exposure to atorvastatin. Therefore, when used concomitantly with moderate CYP3A4 inhibitors, consideration should be given to using a lower maximum dose of atorvastatin and appropriate clinical monitoring of the patient should be conducted. Appropriate clinical monitoring is recommended after initiation or after dose adjustment of the inhibitor.

CYP3A4 Isoenzyme Inducers

Concomitant use of atorvastatin with cytochrome P450 3A4 inducers (e.g., efavirenz, rifampicin, St. John’s wort) may lead to a variable decrease in atorvastatin plasma concentration. Due to the dual mechanism of interaction with rifampicin, since delayed administration of atorvastatin after rifampicin intake was associated with a significant decrease in atorvastatin plasma concentration. However, the effect of rifampicin on atorvastatin concentration in hepatocytes is unknown. If concomitant use is unavoidable, efficacy in patients should be carefully monitored.

Transport Protein Inhibitors

Transport protein inhibitors (e.g., cyclosporine, letermovir) may increase the systemic effect of atorvastatin (see Table 1). The effect of inhibiting hepatic uptake transporters on atorvastatin concentration in hepatocytes is unknown. If concomitant use of these drugs is unavoidable, a reduction in the atorvastatin dose and clinical monitoring of efficacy is recommended (see Table 1).

Atorvastatin is not recommended for patients concomitantly taking letermovir and cyclosporine (see section “Special Instructions”).

Gemfibrozil/Fibrates

The use of fibrate monotherapy has occasionally been associated with muscle-related events, including rhabdomyolysis. The risk of these complications may be increased with the concomitant use of fibrates and atorvastatin. If concomitant use of these drugs is unavoidable, it is recommended to use the minimum effective dose of atorvastatin and to regularly monitor the patient’s condition (see section “Special Instructions”).

Ezetimibe

The use of ezetimibe is associated with the development of adverse reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with the concomitant use of ezetimibe and atorvastatin. Careful monitoring is recommended for such patients.

Colestipol

The plasma concentration of atorvastatin and its active metabolites was lower (approximately 25%) with the concomitant use of colestipol and atorvastatin. However, the effect on lipid levels was greater with the concomitant use of atorvastatin and colestipol than with the use of either drug alone.

Fusidic Acid

Cases of rhabdomyolysis have been reported in patients taking statins and fusidic acid concomitantly. The mechanism of this interaction (whether it is pharmacodynamic, pharmacokinetic, or combined) is unknown. Cases of rhabdomyolysis (sometimes fatal) have been observed in patients receiving this combination. In patients for whom the use of fusidic acid is considered necessary, statin treatment should be discontinued for the entire duration of fusidic acid use (also see “Special Instructions”).

Colchicine

Although studies on the concomitant use of colchicine and atorvastatin have not been conducted, there have been cases of myopathy with this combination. Caution should be exercised when using atorvastatin and colchicine concomitantly.

Ezetimibe

Antacids

Concomitant administration of antacids reduces the rate of absorption of ezetimibe but does not affect its bioavailability. This reduction in absorption rate is not considered clinically significant.

Cholestyramine

Concomitant administration of cholestyramine reduces the mean AUC of total ezetimibe (Ezetimibe + Ezetimibe-glucuronide) by approximately 55%. The additive LDL-C lowering effect of concomitant use of Torvazin^® Plus and cholestyramine may be reduced by this interaction (see section “Dosage and Administration”).

Cyclosporine

In a study of 8 post-renal transplant patients with CrCl greater than 50 ml/min taking a stable dose of cyclosporine, a single 10 mg dose of ezetimibe led to an average 3.4-fold (range 2.3 to 7.9-fold) increase in the AUC of total ezetimibe compared to that in healthy volunteers receiving Ezetimibe in another study (n=17). In another study, one post-renal transplant patient with severe renal impairment taking complex therapy, including cyclosporine, showed a 12-fold increase in total ezetimibe concentration compared to the control group receiving Ezetimibe alone. In a two-period crossover study involving 12 healthy volunteers taking Ezetimibe 20 mg once daily for 8 days with a single 100 mg dose of cyclosporine on day 7, there was an average 15% increase (range from a 10% decrease to a 51% increase) in the AUC of cyclosporine compared to that in healthy volunteers who took a single 100 mg dose of cyclosporine as monotherapy. Controlled studies of the concomitant use of ezetimibe and cyclosporine in post-renal transplant patients have not been conducted. Caution should be exercised when initiating ezetimibe therapy in patients taking cyclosporine. Monitoring of cyclosporine concentration is recommended when used concomitantly with Torvazin^® Plus (see section “Special Instructions”).

Fibrates

When ezetimibe and fenofibrate are used concomitantly, there is a risk of developing cholelithiasis and gallbladder diseases (see sections “Special Instructions” and “Adverse Reactions”).

If cholelithiasis is suspected in patients concomitantly taking Ezetimibe and fenofibrate, a gallbladder examination should be performed and therapy should be discontinued (see section “Adverse Reactions”).

Concomitant administration of fenofibrate and gemfibrozil increases the concentration of total ezetimibe (approximately 1.5-fold and 1.7-fold, respectively).

The safety and efficacy of using ezetimibe concomitantly with other fibrates have not been studied.

Fibrates may increase the biliary excretion of cholesterol, which can lead to the development of cholelithiasis. In preclinical studies in certain animal species, the concentration of cholesterol in bile increased after the use of ezetimibe (see subsection “Preclinical Safety Data”). A relationship between the use of therapeutic doses of ezetimibe and the risk of developing cholelithiasis cannot be excluded.

Effect of Torvazin^® Plus on the Pharmacokinetics of Other Drugs

Atorvastatin

Digoxin

With multiple concomitant administrations of atorvastatin 10 mg and digoxin, the steady-state plasma concentrations of digoxin increased slightly. Patients receiving digoxin require appropriate monitoring.

Oral Contraceptives

Concomitant administration of atorvastatin with oral contraceptives leads to an increase in the plasma concentrations of norethisterone and ethinyl estradiol.

Warfarin

In a clinical study in patients regularly receiving warfarin therapy, concomitant use of atorvastatin 80 mg/day led to a small increase in prothrombin time of approximately 1.7 seconds during the first 4 days of therapy. The indicator returned to normal within 15 days of atorvastatin therapy. Although only in rare cases was a significant interaction affecting anticoagulant function noted, prothrombin time should be determined before starting atorvastatin therapy in patients receiving coumarin anticoagulants and frequently enough during therapy to prevent significant changes in prothrombin time. Once prothrombin time has normalized, its monitoring can be performed as recommended for patients receiving coumarin anticoagulants. When the atorvastatin dose is changed or therapy is discontinued, prothrombin time should be monitored according to the same principles described above. Atorvastatin therapy has not been associated with bleeding or changes in prothrombin time in patients not receiving anticoagulant treatment.

Table 1. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin

¹ Data presented as x-fold change represent the simple ratio of co-administration to atorvastatin monotherapy.

²Concomitant administration of multiple doses of atorvastatin and phenazone resulted in no or minimal effect on the clearance of phenazone.

Ezetimibe

Preclinical studies have shown that Ezetimibe does not induce cytochrome P450 enzymes involved in drug metabolism. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs metabolized by cytochrome P450 isoenzymes 1A2, 2D6, 2C8, 2C9, and 3A4 or by N-acetyltransferase.

In clinical drug interaction studies, coadministration of Ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam. Concomitant administration of cimetidine and ezetimibe had no effect on the bioavailability of ezetimibe.

Anticoagulants

Administration of ezetimibe (10 mg once daily) concomitantly with warfarin did not have a significant effect on the bioavailability of warfarin or on prothrombin time in 12 healthy adult males. Post-marketing reports have been received of increased INR in patients taking Ezetimibe concomitantly with warfarin or fluindione. When Torvazin^® Plus is coadministered with warfarin, other coumarin anticoagulants, or fluindione, regular monitoring of INR is recommended (see section “Special Precautions”).

Storage Conditions

The drug should be stored in the original packaging (blister pack in a cardboard carton) to protect it from moisture, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 30 months.

Dispensing Status

The drug is dispensed 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.