Bemletol EZ

(Bempedoic Acid+Ezetimibe) Tablets

COMPOSITION

Each film coated tablet contains

Bempedoic acid………….. 180mg
Ezetimibe …………..…… 10mg
[Innovator’s Specs.]
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Bemletol EZ tablets, for oral use, contain bempedoic acid, an adenosine triphosphate-citrate lyase (ACL) inhibitor, and ezetimibe, a dietary cholesterol absorption inhibitor.tiktok live apk download

DESCRIPTION

INDICATIONS

Bemletol EZ is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.

DOSAGE AND ADMINISTRATION

Recommended Dosage

The recommended dosage of Bemletol EZ, in combination with maximally tolerated statin therapy, is one tablet orally once daily. One tablet of Bemletol EZ contains 180mg of bempedoic acid and 10mg of ezetimibe. Swallow the tablet whole. Bemletol EZ can be taken with or without food. After initiation of Bemletol EZ, analyze lipid levels within 8 to 12 weeks.

Coadministration with Bile Acid Sequestrants: Administer Bemletol EZ either at least 2 hours before or at least 4 hours after bile acid sequestrants.

CLINICAL PHARMACOLOGY

Mechanism of Action: Bemletol EZ contains bempedoic acid and ezetimibe. Bemletol EZ reduces elevated LDL-C through inhibition of cholesterol synthesis in the liver and absorption in the intestine.

Bempedoic acid

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) by inhibition of cholesterol synthesis in the liver. ACL is an enzyme upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Bempedoic acid and its active metabolite, ESP15228, require coenzyme A (COA) activation by very long-chain acyl-CoA synthetase 1 (ACSVL 1) to ETC-1002-CoA and ESP15228-COA, respectively. ACSVL1 is expressed primarily in the liver. Inhibition of ACL by ETC-1002-CoA results in decreased cholesterol synthesis in the liver and lowers LDL-C in blood via upregulation of low-density lipoprotein receptors.

Ezetimibe

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in LDL receptors, resulting in clearance of cholesterol from the blood.

PHARMACOKINETICS

Absorption

Bempedoic acid

Following single oral administration of 180 mg of bempedoic acid and 10mg of ezetimibe, mean (± SD) Cmax and AUC of bempedoic acid were 12.6 (±2.80) μg/mL and 202 (± 43.4) ug.hr/mL, respectively; the median time to maximum concentration (Tmax) was 3.0 hours. Following multiple-dose administration of bempedoic acid monotherapy, the steady-state maximum plasma concentration (Cmax) and AUC at 180mg/day were 20.6±6.1 μg/ml and 289.0 ± 96.4 μg-h/ml, respectively. Bempedoic acid steady-state pharmacokinetics were generally linear over a range of >60mg to 220mg (approximately 33% to 122% of the recommended dosage of 180mg daily).

Ezetimibe

After a single dose of Bempedoic acid+Ezetimibe to fasted adults, mean ± SD Ezetimibe Cmax of 3.56 ± 1.90ng/ml were attained with a median Tmax of 5 hr. Ezetimibe-glucuronide mean Cmax values of 107 ± 46ng/ml were achieved with a median Tmax of 1 hr. For ezetimibe monotherapy, there was no substantial deviation from dose proportionality between 5mg and 20mg (0.5-to 2-fold the recommended dosage). The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Distribution:
Bempedoic acid: The bempedoic acid apparent volume of distribution (V/F) was 18 L. Plasma protein binding of bempedoic acid, its glucuronide and its active metabolite, ESP15228, were 99.3%, 98.8% and 99.2%, respectively. Bempedoic acid does not partition into blood cells. Ezetimibe: Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

Eliminations

Bempedoic acid

The steady-state clearance (CL/F) of bempedoic acid was 11.2ml/min after once-daily dosing; renal clearance of unchanged bempedoic acid represented less than 2% of total clearance. The mean ± SD half-life for bempedoic acid in humans was 21 ± 11 hours at steady-state.

Ezetimibe

Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half- life of approximately 22 hours for both.

Metabolism

Bempedoic acid

The primary route of elimination for bempedoic acid is through metabolism to the acyl glucuronide. Bempedoic acid is also reversibly converted to an active metabolite (ESP15228) based on aldo-keto reductase activity observed in vitro from human liver. Mean plasma AUC metabolite/parent drug ratio for ESP15228 following repeat-dose administration was 18% and remained constant over time. Both bempedoic acid and ESP15228 are converted to inactive glucuronide conjugates in vitro by UGT2B7. Bempedoic acid, ESP15228 and their respective conjugated forms were detected in plasma with bempedoic acid accounting for the majority (46%) of the AUCO-48h and its glucuronide being the next most prevalent (30%). ESP15228 and its glucuronide represented 10% and 11% of the plasma AUCO-48h, respectively. Ezetimibe: Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation with subsequent biliary and renal excretion. Minimal oxidative metabolism has been observed in all species evaluated.
Rev: 08-24/0

Excretion

Bempedoic acid

Following single oral administration of 240mg of berpedoic acid (1.3 times the approved recommended dose), approximately 70% of the total dose (bernpedoic acid and its metabolites) was recovered in urine, primarily as the acyl glucuronide conjugate of bempedoic acid, and approximately 30% was recovered in feces. Less than 5% of the administered dose was excreted as unchanged bempedoic acid in feces and urine combined.

Ezetimibe

Following oral administration of 14C-ezetimibe (20mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. After 48 hours. there were no detectable levels of radioactivity in the plasma

CONTRAINDICATIONS

Bemletol EZ is contraindicated in patients with a known hypersensitivity to ezetimibe tablets. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe.

WARNINGS AND PRECAUTIONS

Hyperuricemia

Hyperuricemia Bempedoic acid, a component of Bemletol EZ, inhibits renal tubular OAT2 and may increase blood uric acid levels, 26% of bempedoic acid-treated patients with normal baseline uric acid values (versus 9.5% placebo) experienced hyperuricemia one or more times, and 3.5% of patients experienced clinically significant Reference ID: 5247252 hyperuricemia reported as an adverse reaction (versus 1.1% placebo). Increases in uric acid levels usually occurred within the first 4 weeks of treatment initiation and persisted throughout treatment. After 12 weeks of treatment, the mean placebo-adjusted increase in uric acid compared to baseline was 0.8mg/dL for patients treated with bempedoic acid.

Tendon Rupture: Bempedoic acid, a component of Bemletol EZ, is associated with an increased risk of tendon rupture or injury, tendon rupture occurred in 0.5% of patients treated with bempedoic acid versus 0% of placebo-treated patients and involved the rotator cuff (the shoulder), biceps tendon, or Achilles tendon. Tendon rupture occurred within weeks to months of starting bempedoic acid. Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders. Discontinue Bemletol EZ immediately if the patient experiences rupture of a tendon. Consider discontinuing Bemletol EZ if the patient experiences joint pain, swelling, or inflammation. Advise patients to rest at the first sign of tendinitis or tendon rupture and to contact their healthcare provider if tendinitis or tendon rupture symptoms occur. Consider alternative therapy in patients with a history of tendon disorders or tendon rupture.

SIDE EFFECTS

The following are the side effects as described below:

• Hyperuricemia
• Tendon Rupture

DRUG INTERACTIONS

Simvastatin

Clinical Impact

Concomitant use of Bemietol EZ with simvastatin causes an increase in simvastatin concentration and may increase the risk of simvastatin-related myopathy. Intervention: Avoid concomitant use of Bemletol EZ with simvastatin greater than 20mg.

Pravastatin

Clinical Impact

Concomitant use of Bemletol EZ with pravastatin causes an increase in pravastatin concentration and may increase the risk of pravastatin-related myopathy. Intervention: Avoid concomitant use of Bemletol EZ with pravastatin greater than 40 mg.

Cyclosporine

Clinical Impact

Concomitant use of Bemletol EZ and cyclosporine increases ezetimibe and cyclosporine concentrations.

Intervention

Monitor cyclosporine concentrations in patients receiving Bemietol EZ and cyclosporine. 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 Bemletol EZ.

Fibrates

Clinical Impact: Both fenofibrate and ezetimibe may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of Bemletol EZ with fibrates other than fenofibrate is not recommended.

Intervention

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

Cholestyramine

Clinical Impact

Concomitant use of Bemletol EZ and cholestyramine decreases ezetimibe concentration. This may result in a reduction of efficacy.

Intervention

Administer Bemletol EZ either at least 2 hours before or at least 4 hours after bile acid sequestrants.

OVERDOSE

There is no clinical experience with Bemletol EZ overdose.

INSTRUCTIONS

Store below 30°C. Protect from heat, light and moisture. Keep out of the reach of children.

PRESENTATION

Bemletol EZ 180mg/10mg Tablets are available in pack size of 10’s.
ہدایات : ۳۰ ڈگری سینٹی گریڈ سے کم درجہ حرارت پر رکھیں ۔ گرمی روشنی اور نمی سے بچائیں۔ بچوں کی پہنچ سے دور رکھیں ۔
PHARMA
Manufactured by:
NABIQASIM INDUSTRIES (PVT.) LTD.
17/24, Korangi Industrial Area, Karachi-Pakistan.
Rev: 08-24/0