Ezetimibe

Ezetimibe is a Cholesterol absorption inhibitor belonging to Antilipemic Agent.

Ezetimibe is a cholesterol absorption inhibitor used to lower total cholesterol, LDL-C, Apo-B, and non-HDL-C in primary hyperlipidemia and familial Cholesterolemia.

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide means Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

Ezetimibe shows common side effects like Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Ezetimibe is available in the form of an Oral Tablet.

Ezetimibe is available in India, the US, the UK, Singapore, Canada, France, Spain, Russia, Japan, New Zealand, China, and Australia.

Ezetimibe belonging to the Antilipemic Agent acts as a Cholesterol absorption inhibitor.

Ezetimibe inhibits the absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores, and increased clearance of cholesterol from the blood; decreases total C, LDL-cholesterol (LDL-C), ApoB, and triglycerides (TG) while increasing HDL-cholesterol (HDL-C).

The Data on the onset and duration of action of Ezetimibe is not available.

The Tmax and Cmax of Ezetimibe are approximately 4-12 hours (ezetimibe); 1-2 hours (active metabolite) and 3.4-5.5 ng/mL (ezetimibe); 45-71 ng/mL (active metabolite) respectively.

Ezetimibe is available in the form of an Oral Tablet.

Ezetimibe tablet is taken orally usually once daily.

Ezetimibe is used to reduce the amount of cholesterol and fatty substances in the blood. It is either used alone or in combination with other cholesterol-lowering medicines.

Ezetimibe is a Cholesterol absorption inhibitor belonging to Antilipemic Agent.

Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This results in decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores, and increased clearance of cholesterol from the blood.

Ezetimibe is approved for use in the following clinical indications

Adult indications

• Homozygous familial hypercholesterolemia
• Homozygous sitosterolemia
• Primary hyperlipidemia, including heterozygous familial and nonfamilial hyperlipidemia or mixed hyperlipidemia

Pediatric indications

• Hyperlipidemia

Although not approved, there have been certain off-label indications. These include

• Secondary prevention of atherosclerotic cardiovascular events after acute coronary syndrome

Adult Dose

• Homozygous familial hypercholesterolemia

Oral: 10 mg once daily.

• Homozygous sitosterolemia

Oral: 10 mg once daily.

• Primary hyperlipidemia, including heterozygous familial and nonfamilial hyperlipidemia or mixed hyperlipidemia

Oral: 10 mg once daily.

Pediatric indications

• Hyperlipidemia

Children 5 to 9 years:

Oral: 10 mg once daily; dosing based on two studies of monotherapy; a prospective trial (n=17 including six patients ≤9 years) and a retrospective review (n=36, age range: 8 to 17 years) showed significant decreases in total cholesterol and LDL-C; patients were followed up to a mean of 13.6 months, no untoward effects were noted.

Children ≥10 years and Adolescents:

Oral: 10 mg once daily in combination with simvastatin. Has also been shown in small pediatric trials to decrease TC and LDL-C when used as monotherapy as an adjunct to dietary changes.

• Secondary prevention of atherosclerotic cardiovascular events after acute coronary syndrome (off-label)

Oral: 10 mg once daily.

Ezetimibe is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

Mild to severe impairment: No dosage adjustment necessary.

• Dosage Adjustment in Hepatic impairment Patient
  

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): Use of Ezetimibe is not recommended.

Ezetimibe is contraindicated in patients with

• The combination of Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels.
• Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefits with continued use during pregnancy.
• Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require Ezetimibe treatment in combination with a statin should be advised not to nurse their infants.
• Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported with Ezetimibe.

• Use With Statins or Fenofibrate

Concurrent administration of Ezetimibe with a specific statin or fenofibrate should be in accordance with the product labeling for that medication.

• Liver Enzymes

In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 x the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe (0.5%) and placebo (0.3%). In controlled clinical combination studies of Ezetimibe initiated concurrently with a statin, the incidence of consecutive elevations (≥3 x ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe administered with statins and 0.4% for patients treated with statins alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When Ezetimibe is coadministered with a statin, liver tests should be performed at the initiation of therapy and according to the recommendations of the statin. Should an increase in ALT or AST ≥3 x ULN persist, consider withdrawal of Ezetimibe and/or statin.

• Myopathy/Rhabdomyolysis

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with Ezetimibe compared with the relevant control arm (placebo or statin alone). However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. In clinical trials, the incidence of creatine phosphokinase (CPK) > 10 x ULN was 0.2% for Ezetimibe vs. 0.1% for placebo, and 0.1% for Ezetimibe coadministered with a statin vs. 0.4% for statins alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age ( > 65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. In post-marketing experience with Ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Ezetimibe. However, rhabdomyolysis has been reported with Ezetimibe monotherapy and with the addition of Ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level > 10 x the ULN indicates myopathy.

It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

Adverse events were observed in some animal reproduction studies. Use is contraindicated in pregnant women who require combination therapy with an HMG-CoA reductase inhibitor. If treatment for familial hypercholesterolemia is needed during pregnancy, other agents are preferred.

• Common Adverse effects

Increased serum transaminases, Arthralgia, Sinusitis, upper respiratory tract infection, Increased gamma-glutamyl transferase.

• Rare Adverse effects

Erythema multiforme, skin rash, urticaria, Abdominal pain, cholecystitis, cholelithiasis, nausea, pancreatitis, Thrombocytopenia, Autoimmune hepatitis, cholestatic hepatitis, hepatocellular hepatitis, Anaphylaxis, angioedema, Depression, dizziness, headache, paresthesia, Increased creatine phosphokinase in a blood specimen, myalgia, myopathy, rhabdomyolysis.

• Cyclosporine

Caution should be exercised when using Ezetimibe and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and cyclosporine. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by Ezetimibe.

• Fibrates

The efficacy and safety of coadministration of ezetimibe with fibrates other than fenofibrate have not been studied. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

• Fenofibrate

If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder studies are indicated, and alternative lipid-lowering therapy should be considered.

• Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe by approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.

• Coumarin Anticoagulants

If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

The common side effects of Ezetimibe include the following

Common

● Headache, dizziness, diarrhea, sore throat, runny nose, sneezing, joint pain.

Rare

● Hives, rash, Itching, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness, upset stomach, extreme tiredness, unusual bleeding or bruising, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms, muscle pain or weakness, fever, chills, pale or fatty stools, chest pain.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 x the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 x the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.

• Nursing Mothers

It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

• Pediatric Use

The effects of Ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe coadministered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161-351 mg/dL) in the Ezetimibe coadministered with simvastatin group compared to 219 mg/dL (range: 149-336 mg/dL) in the simvastatin monotherapy group. The patients received coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered Ezetimibe and 40-mg simvastatin or 40-mg simvastatin monotherapy for the next 27 weeks, and open-label coadministered Ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

• Geriatric Use

Monotherapy Studies

Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.

Statin Coadministration Studies

Of the 11,308 patients who received Ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

• In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.
• In the event of an overdose, symptomatic and supportive measures should be employed.

Pharmacodynamic

Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%.

The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.

Pharmacokinetics

• Absorption

After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

• Distribution

Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins.

• Metabolism and Excretion

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021445s019lbl.pdf
• https://www.rxlist.com/zetia-drug.htm#indications
• https://reference.medscape.com/drug/zetia-ezetimibe-342454
• https://medlineplus.gov/druginfo/meds/a603015.html#side-effects
• https://go.drugbank.com/drugs/DB00973
• https://www.mims.com/india/drug/info/ezetimibe?type=full&mtype=generic
• https://www.webmd.com/drugs/2/drug-64335/ezetimibe-oral/details
• https://www.practo.com/medicine-info/ezetimibe-737-api
• https://www.uptodate.com/contents/ezetimibe-drug-information#F169534
• https://www.drugs.com/ezetimibe.html#dosage