Klivas Plus film-coated tablets 10 mg + 10 mg blister No. 30

Instructions for use: Klivas Plus film-coated tablets 10 mg + 10 mg blister No. 30

Composition

active ingredients:

10 mg/10 mg: 1 tablet contains 10.4 mg of rosuvastatin calcium, equivalent to 10.0 mg of rosuvastatin and 10.0 mg of ezetimibe;

20 mg/10 mg: 1 tablet contains 20.8 mg of rosuvastatin calcium, equivalent to 20.0 mg of rosuvastatin and 10.0 mg of ezetimibe;

40 mg/10 mg: 1 tablet contains 41.6 mg of rosuvastatin calcium, equivalent to 40.0 mg of rosuvastatin and 10.0 mg of ezetimibe;

excipients:

for tablets 10 mg/10 mg: lactose monohydrate; croscarmellose sodium; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silica; magnesium stearate; tablet coating Opadry Beige 02F270003 (hypromellose 2910 (E 464); iron oxide yellow (E 172); titanium dioxide (E 171); macrogol 4000 (E 1521); talc (E 553b));

for tablets 20 mg/10 mg: lactose monohydrate; croscarmellose sodium; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silica; magnesium stearate; tablet coating Vivacoat PC-2P-308 (hypromellose 6 (E 464); titanium dioxide (E 171); talc (E 553b); macrogol 4000 (E 1521); iron oxide yellow (E 172));

for tablets 40 mg/10 mg: lactose, monohydrate; croscarmellose sodium; povidone K-29/32; sodium lauryl sulfate; microcrystalline cellulose 102; hypromellose 2910; colloidal anhydrous silica; magnesium stearate; tablet coating Opadry White OY-L-28900 (lactose, monohydrate; hypromellose 2910 (E 464); titanium dioxide (E 171); macrogol 4000 (E 1521)).

Dosage form

film-coated tablets.

Basic physicochemical properties.

10 mg/10 mg: beige, round, biconvex, film-coated tablets, approximately 10 mm in diameter, embossed with “EL 4” on one side;

20 mg/10 mg: yellow, round, biconvex, film-coated tablets, approximately 10 mm in diameter, embossed with “EL 3” on one side;

40 mg/10 mg: white, round, biconvex, film-coated tablets, approximately 10 mm in diameter, debossed with “EL 2” on one side.

Pharmacotherapeutic group

Lipid-lowering agents. HMG-CoA reductase inhibitors in combination with other lipid-lowering agents; rosuvastatin and ezetimibe.

ATX code C10B A06.

Pharmacological properties

Pharmacodynamics.

The drug contains ezetimibe and rosuvastatin, two lipid-lowering compounds with complementary mechanisms of action. It reduces elevated levels of total cholesterol (total cholesterol), low-density lipoprotein cholesterol (LDL cholesterol), apolipoprotein B (Apo B), triglycerides (TG), and non-HDL cholesterol (non-HDL cholesterol), and increases high-density lipoprotein cholesterol (HDL cholesterol) by dual inhibition of cholesterol absorption and synthesis.

Rosuvastatin

Mechanism of action

Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, the rate-regulating enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. The primary site of action of rosuvastatin is the liver, the target organ for lowering cholesterol levels.

Rosuvastatin increases the number of hepatic low-density lipoprotein (LDL) receptors on the cell surface, enhancing the uptake and catabolism of LDL, and inhibits the hepatic synthesis of very low-density lipoprotein (VLDL), thus reducing the total number of VLDL and LDL particles.

Ezetimibe

Mechanism of action

Ezetimibe is a member of a new class of lipid-lowering agents that selectively inhibit the intestinal absorption of cholesterol and related plant sterols. Ezetimibe is administered orally and has a mechanism of action that is distinct from other classes of cholesterol-lowering drugs (e.g., statins, bile acid sequestrants (resins), acid-derived fibrates, and plant stanols). The molecular target of ezetimibe is the sterol transporter Niemann-Pick Cl-Like 1 (NPC1L1), which is responsible for the intestinal absorption of cholesterol and phytosterols.

Ezetimibe acts at the brush border of the small intestine, where it inhibits cholesterol absorption, reducing its passage from the intestine to the liver. Statins, in turn, reduce cholesterol synthesis in the liver, and together these mechanisms provide additional cholesterol reduction. In a 2-week clinical trial in 18 patients with hypercholesterolemia, ezetimibe reduced cholesterol absorption by 54% compared with placebo.

Pharmacodynamic effects

Rosuvastatin reduces elevated LDL-C, total cholesterol, and triglycerides, and increases HDL-C. It also reduces Apo B, non-HDL-C, VLDL-C, VLDL-TG, and increases Apo A-I (see Table 1). Rosuvastatin also reduces the LDL-C/HDL-C, total-C/HDL-C, and non-HDL-C/HDL-C ratios, and Apo B/Apo AI.

Table 1

Dose-dependent effect in patients with primary hypercholesterolemia (type IIa and IIb) (adjusted mean change in % from baseline)

The therapeutic effect is manifested within 1 week after the start of the drug, and after 2 weeks of treatment the effect is 90% of the maximum possible. The maximum effect is usually achieved after 4 weeks and is maintained thereafter.

Ezetimibe

A series of preclinical studies were conducted to determine the selectivity of ezetimibe in inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of [14C]-cholesterol without affecting the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl estradiol, or the fat-soluble vitamins A and D.

Epidemiological studies have established a direct relationship between cardiovascular morbidity and mortality and total cholesterol and LDL-cholesterol levels, and an inverse relationship between HDL-cholesterol levels. The use of ezetimibe in combination with a statin effectively reduces the risk of cardiovascular disease in patients with coronary heart disease and a history of ACS.

Concomitant use of rosuvastatin and ezetimibe

Clinical efficacy

The aim of this 6-week, randomized, double-blind, parallel-group clinical trial was to evaluate the safety and efficacy of ezetimibe (10 mg) added to ongoing rosuvastatin therapy compared with the use of gradually increasing doses of rosuvastatin from 5 to 10 mg or from 10 to 20 mg (n = 440). The pooled data demonstrated that the use of ezetimibe added to ongoing rosuvastatin therapy at a dose of 5 mg or 10 mg reduced LDL-C by 21%. In contrast, doubling the dose of rosuvastatin to 10 mg or 20 mg reduced LDL-C by 5.7% (difference between groups 15.2%, p < 0.001).

The use of ezetimibe plus rosuvastatin 5 mg alone reduced LDL cholesterol levels more than rosuvastatin 10 mg alone (difference 12.3%, p < 0.001), and the use of ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol levels more than rosuvastatin 20 mg alone (difference 17.5%, p < 0.001).

A 6-week randomized trial was designed to investigate the efficacy and safety of rosuvastatin 40 mg alone and in combination with ezetimibe 10 mg in patients at high risk of coronary heart disease (n = 469). In the rosuvastatin/ezetimibe group, significantly more patients achieved the target ATP III LDL-cholesterol value (< 100 mg/dL, 94.0% vs. 79.1%, p < 0.001) than in the rosuvastatin monotherapy group. The use of rosuvastatin 40 mg provided effective improvement in the atherogenic lipid profile in this high-risk population.

In a randomized, open-label, 12-week study, the reduction in LDL-C was examined in each treatment group (rosuvastatin 10 mg/ezetimibe 10 mg, rosuvastatin 20 mg/ezetimibe 10 mg, simvastatin 40 mg/ezetimibe 10 mg, simvastatin 80 mg/ezetimibe 10 mg). In the low-dose rosuvastatin combination groups, the reduction from baseline was 59.7%, which was significantly greater than in the low-dose simvastatin combination groups (55.2% (p < 0.05)). Treatment with high-dose rosuvastatin combinations reduced LDL-C by 63.5% compared with 57.4% with high-dose simvastatin combinations (p < 0.001).

Pediatric patients

The European Medicines Agency has waived the obligation to submit the results of studies with the drug for lowering cholesterol in all subsets of the paediatric population (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Combination therapy with rosuvastatin and ezetimibe

Concomitant administration of 10 mg of rosuvastatin and 10 mg of ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC. A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse reactions, cannot be excluded.

Rosuvastatin

Absorption: After oral administration, the maximum concentration of rosuvastatin in the blood plasma is reached after approximately 5 hours. Absolute bioavailability is about 20%.

Distribution: Rosuvastatin is extensively taken up by the liver, which is the primary site of cholesterol synthesis and LDL-C clearance. The volume of distribution of rosuvastatin is approximately 134 L. Almost 90% of rosuvastatin is bound to plasma proteins, primarily albumin.

Excretion. About 90% of a dose of rosuvastatin is excreted unchanged in the feces (consisting of absorbed and unabsorbed active substance), and about 5% is excreted unchanged in the urine. The plasma half-life is approximately 19 hours. The half-life does not increase with the use of rosuvastatin in high doses. The geometric mean plasma clearance is approximately 50 l/h (coefficient of variation 21.7%).

As with other HMG-CoA reductase inhibitors, rosuvastatin enters the liver via the membrane transporter OATP-C. This transporter plays an important role in the hepatic elimination of rosuvastatin.

Linearity. Systemic exposure to rosuvastatin increases in proportion to the dose. No changes in the pharmacokinetic parameters of rosuvastatin were observed after repeated daily doses.

Individual populations

Age and gender: Age and gender had no clinically significant effect on the pharmacokinetics of rosuvastatin in adults. Exposure in children and adolescents with heterozygous familial hypercholesterolemia is similar to or lower than exposure in adult patients with dyslipidemia (see section “Paediatric patients” below).

Race: Pharmacokinetic studies indicate that Asians (Japanese, Chinese, Filipinos, Vietnamese, and Koreans) have an approximately 2-fold increase in median AUC and Cmax of rosuvastatin compared to Caucasians; Indians have an approximately 1.3-fold increase in median AUC and Cmax.

Population pharmacokinetic analysis did not reveal clinically significant differences in pharmacokinetics between Caucasian and Negroid patient groups.

Renal impairment: In a study involving patients with varying degrees of renal impairment, mild to moderate renal disease had no effect on plasma concentrations of rosuvastatin or its N-desmethyl metabolite. In patients with severe renal impairment (creatinine clearance < 30 ml/min), plasma concentrations of rosuvastatin increased 3-fold and those of N-desmethyl increased 9-fold compared with healthy volunteers.

Steady-state plasma concentrations of rosuvastatin in patients undergoing hemodialysis were approximately 50% higher than those in healthy volunteers.

Hepatic impairment: In a study involving patients with varying degrees of hepatic impairment, there was no evidence of increased exposure to rosuvastatin in patients with Child-Pugh scores of 7 or lower. However, two patients with Child-Pugh scores of 8 and 9 had at least a 2-fold increase in systemic exposure compared to patients with lower Child-Pugh scores.

There is no experience with the drug in patients with a score above 9 on the Child-Pugh scale.

Genetic polymorphism. HMG-CoA reductase inhibitors, including rosuvastatin, are metabolized by the transporter proteins OATP1B1 and BCRP. Patients with genetic polymorphisms in SLCO1B1 (OATP1B1) and/or ABCG2 (BCRP) are at risk of increased exposure to rosuvastatin. The SLCO1B1 c.521CC and ABCG2 c.421AA polymorphisms are associated with higher exposure (AUC) to rosuvastatin compared with the SLCO1B1 c.521TT or ABCG2 c.421CC genotypes. Specific genotyping is not routinely used in clinical practice, but a lower daily dose of rosuvastatin/ezetimibe is recommended for patients with these types of polymorphisms.

Pediatric Patients: In two pharmacokinetic studies of rosuvastatin (tablet formulation) in children with heterozygous familial hypercholesterolemia aged 10–17 years or 6–17 years (total of 214 patients), exposure was similar to or lower than that in adult patients. The effect of rosuvastatin was predictable with respect to dose and time over a 2-year period.

Ezetimibe

Absorption: After oral administration, ezetimibe is rapidly absorbed and extensively conjugated to form a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). The mean maximum plasma concentration (Cmax) of ezetimibe-glucuronide is reached after 1–2 hours, and of ezetimibe after 4–12 hours. The absolute bioavailability of ezetimibe cannot be determined because the compound is practically insoluble in aqueous media suitable for injection.

Concomitant food intake (low or high fat) does not affect the oral bioavailability of ezetimibe. Ezetimibe can be taken without regard to meals.

Distribution: Ezetimibe and ezetimibe-glucuronide are 99.7% and 88–92% bound to human plasma proteins, respectively.

Elimination: Following oral administration of 20 mg of 14C-ezetimibe to volunteers, total ezetimibe accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactive dose were excreted in the feces and urine, respectively, within 10 days. No measurable levels of radioactivity were observed in plasma after 48 hours.

Individual populations

Age and gender. In elderly patients (65 years and older), plasma concentrations of total ezetimibe are approximately twice those in younger patients (18–45 years). In elderly patients and young patients receiving ezetimibe, the reduction in LDL-C and the safety profile are comparable. Therefore, no dose adjustment is necessary in elderly patients. In women, plasma concentrations of total ezetimibe are slightly higher (approximately 20%) than in men. In men and women receiving ezetimibe, the reduction in LDL-C and the safety profile are comparable. Therefore, gender does not warrant dose adjustment.

Renal Impairment: Following administration of a single 10 mg dose of ezetimibe to patients with severe renal disease (n = 8; mean creatinine clearance ≤ 30 mL/min/1.73 m2), the mean AUC of total ezetimibe increased approximately 1.5-fold compared to healthy volunteers (n = 9). This finding is not considered clinically significant. No dose adjustment is necessary for patients with renal impairment.

In this study, one patient (who received multiple medications, including cyclosporine, after renal transplantation) had a 12-fold higher exposure to total ezetimibe.

Hepatic Impairment: Following a single 10 mg dose of ezetimibe, the mean AUC of total ezetimibe increased approximately 1.7-fold compared to healthy subjects following administration of a single 10 mg dose to patients with mild hepatic impairment (Child-Pugh score 5 or 6). In a 14-day study in which ezetimibe was administered at a dose of 10 mg daily, the mean AUC of total ezetimibe increased approximately 4-fold on days 1 and 14 compared to healthy subjects in patients with moderate hepatic impairment (Child-Pugh score 7–9). No dose adjustment is necessary in patients with mild hepatic impairment. Due to the unknown impact of increased ezetimibe exposure, the drug is not recommended for use in patients with moderate or severe hepatic impairment (> 9 points on the Child-Pugh scale).

Pediatric Patients. The pharmacokinetics of ezetimibe are similar in children ≥ 6 years of age and adults. Pharmacokinetic data are not available in children < 6 years of age. Clinical experience in children and adolescents includes patients with homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, and sitosterolemia.

Indication

Primary hypercholesterolemia

The drug Klivas® Plus is indicated as an adjunct to diet for the treatment of primary hypercholesterolemia (type IIa, including heterozygous familial hypercholesterolemia) in adult patients in whom adequate disease control is achieved with the simultaneous use of rosuvastatin and ezetimibe as monocomponent drugs in the same doses as the fixed combination.

Prevention of cardiovascular diseases

Klivas® Plus is indicated for replacement therapy in adult patients whose condition is adequately controlled with concomitant use of rosuvastatin and ezetimibe as separate drugs in the same doses as in the combination drug, to reduce the risk of cardiovascular disease in patients with ischemic heart disease (IHD) and a history of acute coronary syndrome (ACS).

Contraindication

Hypersensitivity to the active substance (rosuvastatin, ezetimibe) or to any of the excipients of the drug.

Active liver disease, including persistent elevations of serum transaminases of unknown etiology and elevations of any serum transaminase to more than 3 times the upper limit of normal (ULN) (see section "Special warnings and precautions for use").

Pregnancy, breast-feeding. The drug is contraindicated in women of reproductive age who are not using adequate contraception (see section "Use during pregnancy or breast-feeding").

Severe renal impairment (creatinine clearance < 30 ml/min).

Myopathy (see section "Special warnings and precautions for use").

Concomitant use with the combination of sofosbuvir/velpatasvir/voxilaprevir (see section “Interaction with other medicinal products and other types of interactions”).

Concomitant therapy with cyclosporine (see section "Interaction with other medicinal products and other types of interactions").

The 40 mg/10 mg dose is contraindicated in patients with risk factors for myopathy/rhabdomyolysis. These include:

moderate renal impairment (creatinine clearance < 60 ml/min);

hypothyroidism;

hereditary muscle diseases in personal or family history;

history of muscle toxicity caused by other HMG-CoA reductase inhibitors or fibrates;

alcohol abuse;

the patient's Asian origin;

concomitant use of fibrates (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Interaction with other medicinal products and other types of interactions

Associated with rosuvastatin

Effect of concomitant medications on rosuvastatin

Transport protein inhibitors

Rosuvastatin is a substrate for several transport proteins, including the hepatic uptake transporter OATP1B1 and the efflux transporter BCRP. Concomitant use of rosuvastatin with medicinal products that inhibit these transport proteins may lead to increased plasma concentrations of rosuvastatin and an increased risk of myopathy (see sections 4.2, 4.4, and 4.5).

Ticagrelor

Ticagrelor may cause renal failure and affect the renal excretion of rosuvastatin, increasing the risk of its accumulation. In some cases, concomitant administration of ticagrelor and rosuvastatin has resulted in decreased renal function, increased creatine phosphokinase (CPK) levels, and rhabdomyolysis. Monitoring of renal function and CPK levels is recommended when ticagrelor and rosuvastatin are used concomitantly.

Cyclosporine

When rosuvastatin and ciclosporin were co-administered, rosuvastatin AUC values were on average approximately 7-fold higher than those observed in healthy volunteers (see Table 2). Rosuvastatin is contraindicated in patients receiving concomitant ciclosporin (see section 4.3).

Concomitant use of rosuvastatin and cyclosporine did not affect the plasma concentration of cyclosporine.

Protease inhibitors

Although the exact mechanism of interaction is unknown, concomitant use of protease inhibitors may significantly increase rosuvastatin exposure (see Table 2). For example, in a pharmacokinetic study, co-administration of 10 mg of rosuvastatin and a combination product containing two protease inhibitors (300 mg atazanavir/100 mg ritonavir) in healthy volunteers was accompanied by an increase in rosuvastatin AUC and Cmax by approximately 3- and 7-fold, respectively. Concomitant use of rosuvastatin and some combinations of protease inhibitors is possible after careful dose adjustment of rosuvastatin due to the expected increase in its exposure (see sections “Method of administration and dosage”, “Special instructions for use”, “Interaction with other medicinal products and other forms of interaction”, Table 2).

Gemfibrozil and other lipid-lowering agents

Concomitant use of rosuvastatin and gemfibrozil leads to a doubling of rosuvastatin Cmax and AUC (see section "Special warnings and precautions for use").

Based on data from specific studies, no pharmacokinetically significant interaction with fenofibrate is expected, but a pharmacodynamic interaction is possible. Gemfibrozil, fenofibrate, other fibrates and lipid-lowering doses (≥ 1 g/day) of niacin (nicotinic acid) increase the risk of myopathy when used concomitantly with HMG-CoA inhibitors, probably because they can cause myopathy when used alone. The 40 mg dose is contraindicated with concomitant use of fibrates (see sections 4.3 and 4.4). Such patients should also start rosuvastatin therapy at a dose of 5 mg.

Ezetimibe

Co-administration of 10 mg of rosuvastatin and 10 mg of ezetimibe in patients with hypercholesterolemia resulted in a 1.2-fold increase in rosuvastatin AUC (see Table 2). A pharmacodynamic interaction between rosuvastatin and ezetimibe, which could lead to adverse reactions, cannot be excluded (see section 4.4).

Antacids

Concomitant administration of rosuvastatin with an antacid suspension containing aluminum and magnesium hydroxide resulted in a decrease in plasma concentrations of rosuvastatin by approximately 50%. This effect was less pronounced when the antacid was administered 2 hours after rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin

Concomitant use of rosuvastatin and erythromycin resulted in a 20% decrease in rosuvastatin AUC and a 30% decrease in Cmax. This interaction may be due to increased intestinal motility due to erythromycin.

Cytochrome P450 enzymes

In vitro and in vivo studies indicate that rosuvastatin is not an inhibitor or inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a weak substrate of these isoenzymes. Therefore, interactions resulting from metabolism associated with cytochrome P450 enzymes are not expected. No clinically significant interactions were observed between rosuvastatin and fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4).

If it is necessary to use rosuvastatin with other drugs that can increase the exposure of rosuvastatin, the dose of rosuvastatin should be adjusted. If it is expected that the exposure of the drug (AUC) will increase by approximately 2 or more times, the use of rosuvastatin should be started at a dose of 5 mg once a day. The maximum daily dose of rosuvastatin should be adjusted so that the expected exposure of rosuvastatin does not exceed the exposure observed when taking a dose of 40 mg / day without the use of drugs that interact with rosuvastatin; for example, when used with gemfibrozil, the dose of rosuvastatin will be 20 mg (an increase in exposure of 1.9 times), when used with the combination of ritonavir / atazanavir - 10 mg (an increase of 3.1 times).

If the drug increases the AUC of rosuvastatin by less than 2 times, the initial dose does not need to be reduced, but caution should be exercised when increasing the dose of rosuvastatin to more than 20 mg.

Table 2

Effect of concomitant medications on rosuvastatin exposure (AUC; in descending order of magnitude) based on published clinical trial data

* Data presented as x-fold change represents the ratio between rosuvastatin in combination and alone. Data presented as % change represents the % difference relative to rosuvastatin alone.

Increase is indicated by the ↑ icon, decrease by the ↓ icon.

** Several interaction studies have been conducted at different doses of rosuvastatin, the most significant relationship is presented in Table 2.

Drugs/combinations that had no clinically significant effect on rosuvastatin AUC when co-administered: aleglitazar 0.3 mg for 7 days; fenofibrate 67 mg 3 times a day, 7 days; fluconazole 200 mg 1 time a day, 11 days; fosamprenavir 700 mg / ritonavir 100 mg 2 times a day, 8 days; ketoconazole 200 mg 2 times a day, 7 days; rifampin 450 mg 1 time a day, 7 days; silymarin 140 mg 3 times a day, 5 days.

Effect of rosuvastatin on concomitant medications

Oral contraceptives/hormone replacement therapy (HRT). Concomitant use of rosuvastatin and oral contraceptives resulted in an increase in the AUC of ethinylestradiol and norgestrel by 26% and 34%, respectively. When selecting the dose of oral contraceptives, such increases in plasma levels of drugs should be taken into account. There are no data on the pharmacokinetics of drugs in patients receiving rosuvastatin and HRT simultaneously, therefore, the effect of rosuvastatin on the pharmacokinetics of HRT cannot be excluded. However, this combination has been widely used in women in clinical trials and was well tolerated.

Other medicines

Digoxin

According to special studies, no clinically significant interaction with digoxin is expected.

Fusidic acid

Interaction studies of rosuvastatin with fusidic acid have not been conducted. The risk of myopathy, including rhabdomyolysis, may be increased when systemic fusidic acid is administered concomitantly with statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Rhabdomyolysis (including fatal outcomes) has been reported in patients receiving this combination.

If the use of systemic fusidic acid is necessary, rosuvastatin therapy should be discontinued for the entire period of fusidic acid treatment (see also section "Special warnings and precautions for use").

Related to ezetimibe

In nonclinical studies, ezetimibe has been shown not to induce cytochrome P450 drug-metabolizing enzymes. No clinically significant pharmacokinetic interactions were observed between ezetimibe and drugs known to be metabolized by cytochrome P450 1A2, 2D6, 2C8, 2C9, and 3A4 or N-acetyltransferase.

In clinical interaction studies, ezetimibe did not affect the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam when coadministered with ezetimibe. Cimetidine did not affect the bioavailability of ezetimibe when coadministered with ezetimibe.

Antacids

Concomitant administration of antacids decreased the rate of absorption of ezetimibe, but did not affect its bioavailability. This decrease in the rate of absorption is not considered clinically significant.

Cholestyramine

Coadministration of cholestyramine decreased the mean AUC of total ezetimibe (ezetimibe + ezetimibe glucuronide) by approximately 55%. This interaction may account for the incremental reduction in low-density lipoprotein cholesterol (LDL-C) levels caused by the addition of ezetimibe to cholestyramine (see Dosage and Administration).

Fibrates

Physicians should be aware of the potential risk of cholelithiasis and gallbladder disease in patients receiving fenofibrate and ezetimibe (see sections 4.4 and 4.8). If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder examination should be performed and therapy discontinued (see section 4.8). Concomitant administration of fenofibrate or gemfibrozil modestly increased total ezetimibe concentrations (approximately 1.5- and 1.7-fold, respectively).

The concomitant use of ezetimibe with other fibrates has not been studied.

Fibrates may increase the excretion of cholesterol into the bile, leading to the development of gallstone disease. In animal studies, ezetimibe has occasionally increased cholesterol levels in gallbladder bile, but not in all species. A lithogenic risk associated with the therapeutic use of ezetimibe cannot be excluded.

Statins

No clinically significant pharmacokinetic interactions were observed when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.

Cyclosporine

In a study of eight renal transplant patients with creatinine clearance > 50 mL/min who were receiving stable doses of cyclosporine, a single dose of 10 mg