What is mechanism of action?

mechanism of action is Hydroxymethylglutaryl-CoA Reductase Inhibitors [MoA]

Simvastatin

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Simvastatin Prescribing Information

Dosage and Administration (

2.1 Important Dosage and Administration Information

Take simvastatin tablet orally once daily in the evening.
The maximum recommended dosage is simvastatin tablet 40 mg once daily
[see Dosage and Administration (2.2, 2.3)].
An 80 mg daily dosage of simvastatin tablet is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablet 40 mg daily, prescribe alternative LDL-C-lowering treatment.
Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets, and adjust the dosage if necessary.

)

3/2023

Simvastatin tablet 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 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 LDL-C in adults with homozygous familial hypercholesterolemia (HoFH).

• As an adjunct to diet for the treatment of adults with:

      o Primary dysbetalipoproteinemia.

      o Hypertriglyceridemia.

Important Dosage and Administration Information: (
2.1 Important Dosage and Administration Information
Take simvastatin tablet orally once daily in the evening.
The maximum recommended dosage is simvastatin tablet 40 mg once daily
[see Dosage and Administration (2.2, 2.3)].
An 80 mg daily dosage of simvastatin tablet is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].
If as dose is missed, take the missed dose as soon as possible. Do not double the next dose.
For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablet 40 mg daily, prescribe alternative LDL-C-lowering treatment.
Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets, and adjust the dosage if necessary.
)
- Take simvastatin tablet orally once daily in the evening.
- Maximum recommended dosage is simvastatin tablet 40 mg once daily. An 80 mg daily dosage of simvastatin tablet is restricted to patients who have been taking simvastatin 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity.
- For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablet 40 mg daily, prescribe alternative LDL-C lowering treatment.
- Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating, and adjust the dosage if necessary.
Adults:
Recommended dosage is 20 mg to 40 mg once daily. (

2.2 Recommended Dosage in Adult Patients
The recommended dosage range of simvastatin tablet is 20 mg to 40 mg once daily.
)
Pediatric Patients Aged 10 Years and Older with HeFH
: Recommended dosage is 10 mg to 40 mg once daily. (

2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH
The recommended dosage range of simvastatin tablet is 10 mg to 40 mg daily.
)
Patients with Severe Renal Impairment:
Recommended starting dosage is simvastatin 5 mg once daily. (

2.4 Recommended Dosage in Patients with Renal Impairment
For patients with severe renal impairment [creatinine clearance (CL_cr) 15 to 29 mL/min], the recommended starting dosage of simvastatin is 5 mg once daily
[see Warnings and Precautions (5.1)and Use in Specific Populations (8.6)].
Use another simvastatin product to initiate dosing in such patients.
There are no dosage adjustment recommendations for patients with mild or moderate renal impairment.
,

8.6 Renal Impairment
Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment (CLcr 15 to 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [
see Dosage and Administration , Warnings and Precautions
].
)
See full prescribing information for simvastatin dosage modifications due to drug interactions. (

2.5 Dosage Modifications Due to Drug Interactions
Concomitant use of simvastatin tablets with the following drugs requires dosage modification of simvastatin tablets
[see Warnings and Precautions (5.1)and Drug Interactions (7.1)].
Patients taking Lomitapide
Reduce the dosage of simvastatin tablets by 50%. Do not exceed simvastatin tablets 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of simvastatin tablets chronically while taking lomitapide)
[see Dosage and Administration (2.1)].
Patients taking Verapamil, Diltiazem, or Dronedarone
Do not exceed simvastatin tablets 10 mg once daily.
Patients taking Amiodarone, Amlodipine, or Ranolazine
Do not exceed simvastatin tablets 20 mg once daily.
)

Simvastatin tablets USP 5 mg are brick red colored, round shaped, biconvex, film coated tablet debossed “SI” on one side and plain on other side.
Simvastatin tablets USP 10 mg are brick red colored, oval shaped, biconvex, film-coated tablets, debossed “S 4” on one side and plain on the other side.
Simvastatin tablets USP 20 mg are brick red colored, oval shaped, biconvex, film-coated tablets, debossed “S 5” on one side and plain on the other side.
Simvastatin tablets USP 40 mg are brick red colored, oval shaped, biconvex, film-coated tablets, debossed “S 6” on one side and plain on the other side.
Simvastatin tablets USP 80 mg are brick red colored, capsule shaped, biconvex, film-coated tablets, debossed with “SMV” on one side and “80” on the other side.

Pregnancy:
May cause fetal harm. (

8.1 Pregnancy
Risk Summary

Discontinue simvastatin tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient.

Simvastatin tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [
see Clinical Pharmacology
]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients.

Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with simvastatin tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage
(see Data)
.

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m²)
(see Data)
.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data
A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births.

Animal Data
Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6 to 17 and to pregnant rabbits from gestation days 6 to 18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits.

Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested.

Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta.
)
Lactation:
Breastfeeding not recommended during treatment with simvastatin tablets. (

8.2 Lactation
Risk Summary
There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including simvastatin tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with simvastatin tablets[
see Use in Specific Populations , Clinical Pharmacology
].
)

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

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Tablets

Simvastatin tablet is a substrate of CYP3A4 and of the transport protein OATP1B1. Simvastatin tablets exposure can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with simvastatin tablets and instructions for preventing or managing them

[see Warnings and Precautions (5.1)and Clinical Pharmacology (12.3).]

Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Tablets

Strong CYP3A4 inhibitors
Clinical Impact:	Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with simvastatin increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher simvastatin dosages.
Intervention:	Concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated [see Contraindications ]. If treatment with a CYP3A4 inhibitor is unavoidable, suspend simvastatin during the course of strong CYP3A4 inhibitor treatment.
Examples:	Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone.
Cyclosporine, Danazol, or Gemfibrozil
Clinical Impact:	The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin. Gemfibrozil may cause myopathy when given alone.
Intervention:	Concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin is contraindicated [see Contraindications ].
Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers
Clinical Impact:	The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with simvastatin.
Intervention:	For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg daily . For patients taking amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily [see Dosage and Administration ].
Lomitapide
Clinical Impact:	Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased .
Intervention:	Reduce the dose of simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin chronically) while taking lomitapide [see Dosage and Administration ].
Daptomycin
Clinical Impact:	Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration.
Intervention:	If treatment with daptomycin is required, consider temporarily suspending simvastatin during the course of daptomycin treatment.
Niacin
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with simvastatin. The risk of myopathy is greater in Chinese patients. In a clinical study (median follow-up 3.9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin.
Intervention:	Concomitant use of simvastatin with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations ]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with simvastatin.
Intervention:	Consider if the benefit of using fibrates concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with simvastatin.
Intervention:	Consider if the benefit of using colchicine concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact:	Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention:	Avoid grapefruit juice when taking simvastatin.

Concomitant use of cyclosporine, danazol or gemfibrozil