Ezetimibe and Simvastatin

EZETIMIBE AND SIMVASTATIN- ezetimibe and simvastatin tablet
Glenmark Pharmaceuticals Inc., USA

1 INDICATIONS AND USAGE

Ezetimibe and Simvastatin Tablets
Ezetimibe and Simvastatin Tablets are combination of simvastatin and ezetimibe indicated:
Simvastatin
Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.
As an adjunct to diet to reduce elevated low density lipoprotein cholesterol (LDL-C):
o
In adults with primary hyperlipidemia.
o
In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to other LDL-C-lowering therapies to reduce elevated LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).

Simvastatin

Simvastatin, when used as a component of ezetimibe and simvastatin tablets, is indicated to reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

o
Take ezetimibe and simvastatin tablets orally once daily in the evening with or without food.
o
The maximum recommended dosage is ezetimibe and simvastatin tablets 10/40 mg once daily. The ezetimibe and simvastatin tablets 10/80 mg daily dosage is restricted to adult patients who have been taking ezetimibe and simvastatin tablets 10/80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
o
For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving ezetimibe and simvastatin tablets 10/40 mg daily, prescribe alternative LDL-C-lowering treatment.
o
If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
o
Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ezetimibe and simvastatin tablets, and adjust the dosage if necessary.

2.2 Recommended Dosage in Adult Patients

The recommended dosage range of ezetimibe and simvastatin tablets 10/10 mg to 10/40 mg once a day.

2.3 Recommended Dosage in Pediatric Patients10 Years of Age and Older with HeFH

The recommended dosage range of ezetimibe and simvastatin tablets 10/10 mg to 10/40 mg once a day.

2.4 Recommended Dosage in Patients with Renal Impairment

Renal impairment is a risk factor for statin-associated myopathy. Doses of ezetimibe and simvastatin tablets exceeding 10/20 mg should be used with caution and close monitoring in patients with moderate to severe renal impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
There are no dosage adjustment recommendations for patients with mild renal impairment.

2.5 Dosage Modifications Due to Drug Interactions

Concomitant use of ezetimibe and simvastatin tablets with the following drugs requires dosage modification of ezetimibe and simvastatin tablets [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
Patients taking Lomitapide
Reduce the dosage of ezetimibe and simvastatin tablets by 50%. Do not exceed ezetimibe and simvastatin tablets 10/20 mg once daily (or 10/40 mg once daily for patients who have previously taken ezetimibe and simvastatin tablets 10/80 mg daily chronically while taking lomitapide) [see Dosage and Administration (2.1)].
Patients taking Verapamil, Diltiazem, or Dronedarone
Do not exceed ezetimibe and simvastatin tablets 10/10 mg once daily.
Patients taking Amiodarone, Amlodipine, or Ranolazine
Do not exceed ezetimibe and simvastatin tablets 10/20 mg once daily.
Patients taking Bile Acid Sequestrants
In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or 4 hours after the bile acid sequestrant.

3 DOSAGE FORMS AND STRENGTHS

Ezetimibe and simvastatin tablets:
Ezetimibe and Simvastatin Tablets 10 mg/10 mg are white to off-white, capsule shaped, uncoated tablets debossed with ‘G’ on one side and ‘321’ on the other side.
Ezetimibe and Simvastatin Tablets 10 mg/20 mg are white to off-white, capsule shaped, uncoated tablets
debossed with ‘G’ on one side and ‘322’ on the other side.
Ezetimibe and Simvastatin Tablets 10 mg/40 mg are white to off-white, capsule shaped, uncoated tablets debossed with ‘G’ on one side and ‘323’ on the other side.
Ezetimibe and Simvastatin Tablets 10 mg/80 mg are white to off-white, capsule shaped, uncoated tablets debossed with ‘G’ on one side and ‘324’ on the other side.

4 CONTRAINDICATIONS

Ezetimibe and simvastatin tablets are contraindicated in the following conditions:

Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see Drug Interactions (7.1)].
Concomitant use of cyclosporine, danazol, or danazol [see Drug Interactions (7.1)].
Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].
Hypersensitivity to simvastatin, ezetimibe, or any excipients in ezetimibe and simvastatin tablets. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome, have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Myopathy and Rhabdomyolysis

Ezetimibe and simvastatin tablets may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including ezetimibe and simvastatin tablets.
In clinical trials of 24,747 simvastatin-treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10 X ULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical trial of 12,064 simvastatin-treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40 X ULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [see Adverse Reactions (6.1)].
In the Trial of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablets 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) was 0.2% for ezetimibe and simvastatin tablets and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for ezetimibe and simvastatin tablets and 0.02% for placebo.
In postmarketing 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 fibric acid derivatives. Ezetimibe and simvastatin tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected.
Risk Factors for Myopathy
Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher ezetimibe and simvastatin tablets dosage; Chinese patients on ezetimibe and simvastatin tablets may be at higher risk for myopathy [see Contraindications (4), Drug Interactions (7.1), and Use in Specific Populations (8.8)]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking ezetimibe and simvastatin tablets 80 mg daily compared with patients taking lower ezetimibe and simvastatin tablets dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see Adverse Reactions (6.1)].
Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
The concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets are contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend ezetimibe and simvastatin tablets during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of ezetimibe and simvastatin tablets with gemfibrozil, cyclosporine, or danazol is also contraindicated [see Contraindications (4) and Drug Interactions (7.1)].
Ezetimibe and simvastatin tablets dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see Dosage and Administration (2.5)]. ezetimibe and simvastatin tablets use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1)].
Use the 80 mg daily dosage of ezetimibe and simvastatin tablets only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see Dosage and Administration (2.1)]. If patients treated with ezetimibe and simvastatin tablets 80 mg are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [see Drug Interactions (7.1)].
Discontinue ezetimibe and simvastatin tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if ezetimibe and simvastatin tablets are discontinued. Temporarily discontinue ezetimibe and simvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ezetimibe and simvastatin tablets dosage and advise patients receiving ezetimibe and simvastatin tablets 80 mg of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

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