Simastin N

Uses

Primary hypercholesterolemia / mixed dyslipidemia / hypertriglyceridemia: Reduce total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides (TG), or increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia in combination with standard cholesterol-lowering diet when simvastatin or niacin monotherapy is inadequate

Simastin N is also used to associated treatment for these conditions: Atherosclerosis, Mixed Dyslipidemias, Myocardial Infarction, Pellagra, Vitamin Deficiency, Primary Hyperlipidemia, Severe Hyperlipidemia, Dietary supplementationCardiovascular Events, Diabetes Mellitus, Heterozygous Familial Hypercholesterolemia, High Cholesterol, Homozygous Familial Hypercholesterolemia, Mixed Hyperlipidemia, History of coronary heart disease cardiovascular event, History of stroke or other cerebrovascular disease cardiovascular event

How Simastin N works

Niacin performs a number of functions in the body and so has many mechanisms, not all of which have been fully described. Niacin can decrease lipids and apolipoprotein B (apo B)-containing lipoproteins by modulating triglyceride synthesis in the liver, which degrades apo B, or by modulating lipolysis in adipose tissue.

Niacin inhibits hepatocyte diacylglycerol acyltransferase-2. This action prevents the final step of triglyceride synthesis in hepatocytes, limiting available triglycerides for very low density lipoproteins (VLDL). This activity also leads to intracellular degradation of apo B and decreased production of low density lipoproteins, the catabolic product of VLDL.

Niacin also inhibits a high density lipoprotein (HDL) catabolism receptor, which increases the levels and half life of HDL.

Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed in vivo to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Simvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Simvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL.

At therapeutic doses, the HMG-CoA enzyme is not completely blocked by simvastatin activity, thereby allowing biologically necessary amounts of mevalonate to remain available. As mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with simvastatin would also not be expected to cause any accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.

In vitro and in vivo animal studies also demonstrate that simvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Dosage

Simastin N dosage

Primary hypercholesterolemia / mixed dyslipidemia / hypertriglyceridemia:

Initial dose: Not for use as initial therapy of dyslipidemias. Doses should be individualized according to the baseline LDL-cholesterol levels, the recommended goal of therapy, and the patient's response.

Patients naïve to niacin ER therapy or currently on immediate-release niacin:Niacin ER 500 mg/simvastatin 20 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin.

Patients currently on simvastatin (20 to 40 mg daily):Niacin ER 500 mg/simvastatin 40 mg once daily at bedtime; increase dose every 4 weeks as needed in increments of not more than 500 mg of niacin.

Maintenance dose: Niacin ER 1,000 to 2,000 mg/simvastatin 20 to 40 mg once daily (maximum daily dose: niacin ER 2,000 mg/simvastatin 40 mg).

Note:If therapy is interrupted for >7 days, reinstitution of therapy should begin with the lowest dose followed by retitration as tolerated. May be substituted for equivalent dose of niacin extended-release, however, manufacturer does not recommend direct substitution with immediate-release preparations.Dosage adjustment with concomitant medications:

• Amiodarone, amlodipine, or ranolazine: Maximum: Niacin ER 1,000 mg/simvastatin 20 mg per day
• Lomitapide: Reduce simvastatin dose by 50% when initiating lomitapide. Simvastatin dose should not exceed 20 mg/day (or 40 mg daily for those who previously tolerated simvastatin 80 mg daily for ≥1 year without evidence of muscle toxicity).

Administer tablets whole; do not break, crush or chew. Administer with a low-fat snack at bedtime. To attenuate flushing symptoms, may premedicate with aspirin 30 minutes before dose; avoid ingestion of alcohol, hot or spicy foods/liquids concurrently with niacin.

Side Effects

Common side effects are Flushing, Headache, Pruritus, Diarrhea, nausea, Back pain

Toxicity

Overdose of niacin may present with severe prolonged hypotension. Patients experiencing an overdose should be treated with supportive measures which may include intravenous fluids.

The oral LD₅₀ in the mouse is 3720mg/kg, in the rabbit is 4550mg/kg, in the rat is 7000mg/kg, and the dermal LD₅₀ in the rat is >2000mg/kg.

Precaution

Before instituting therapy with Niacin, an attempt should be made to control hyperlipidemia with appropriate diet, exercise, and weight reduction in obese patients and to treat other underlying medical problems. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niacin therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycemic therapy may be necessary.

Caution should also be used when Niacin is used in patients with unstable angina or in the acute phase of MI, particularly when such patients are also receiving vasoactive drugs such as nitrates, calcium channel blockers or adrenergic blocking agents. Elevated uric acid levels have occurred with Niacin therapy, therefore use with caution in patients predisposed to gout. Niacin has been associated with small but statistically significant dose-related reductions in platelet count and increases in prothrombin time. Caution should be observed when Niacin is administered concomitantly with anticoagulants; prothrombin time and platelet counts should be monitored closely in such patients. Niacin has been associated with small but statistically significant, dose-related reductions in phosphorus levels (mean of -13% with 2000 mg). So phosphorus levels should be monitored periodically in patients at risk.

• If there is a history of liver disease
• Who take high alcohol
• Liver function test should be done before and during treatment
• If serum transaminase rises three times the upper limit of normal, treatment should be discontinued
• Avoid pregnancy during and for one month after treatment

Interaction

Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension. Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear. About 98% of available Niacin was bound to colestipol, with 10 to 30% binding to cholestyramine. These results suggest that 4 to 6 hours, or as great an interval as possible, should elapse between the ingestion of bile acid-binding resins and the administration of Niacin.

Digoxin: Concomitant administration of Simvastatin and Digoxin in normal volunteers resulted in a slight elevation (less than 0.3 µgm/ml) in drug concentrations in plasma compared to concomitant administration of placebo and Digoxin.

Coumarin derivatives: Slightly enhance the anticoagulant effect of Warfarin (mean changes in p rothrombin time less than two seconds) in normal volunteers maintained in a state of low therapeutic anticoagulation.

Others: In clinical studies, Simvastatin was used concomitantly with ACE inhibitors, beta-blockers, calcium channel blockers, diuretics and NSAIDs without evidence of clinically significant adverse interactions.

Volume of Distribution

Data regarding the volume of distribution of niacin is not readily available.

Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

Elimination Route

In patients with chronic kidney disease, the C_max is 0.06µg/mL for a 500mg oral dose, 2.42µg/mL for a 1000mg oral dose, and 4.22µg/mL for a 1500mg oral dose. The T_max is 3.0 hours for a 1000mg or 1500mg oral dose. The AUC is 1.44µg*h/mL for a 500mg oral dose, 6.66µg*h/mL for a 1000mg oral dose, and 12.41µg*h/mL for a 1500mg oral dose. These values did not drastically differ in patients requiring dialysis.

Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours post-dose. While the recommended therapeutic dose range is 10 to 40 mg/day, there was no substantial deviation from linearity of AUC with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.

In a pharmacokinetic study of 17 healthy Chinese volunteers, the major PK parameters were as follows: Tmax 1.44 hours, Cmax 9.83 ug/L, t1/2 4.85 hours, and AUC 40.32ug·h/L.

Simvastatin undergoes extensive first-pass extraction in the liver, the target organ for the inhibition of HMG-CoA reductase and the primary site of action. This tissue selectivity (and consequent low systemic exposure) of orally administered simvastatin has been shown to be far greater than that observed when the drug is administered as the enzymatically active form, i.e. as the open hydroxyacid.

In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the bioavailability of the drug in the systemic system is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reached the general circulation in the form of active inhibitors.

Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact simvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that simvastatin plasma concentrations were increased on average 3.2-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin.

For patients known to have the above-mentioned c.521CC OATP1B1 genotype, a maximum daily dose of 20mg of simvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Evidence has also been obtained with other statins such as rosuvastatin that concurrent use of statins and inhibitors of Breast Cancer Resistance Protein (BCRP) such as elbasvir and grazoprevir increased the plasma concentration of these statins. Further evidence is needed, however a dose adjustment of simvastatin may be necessary. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Half Life

The half life of niacin is 0.9h, nicotinuric acid is 1.3h, and nicotinamide is 4.3h.

4.85 hours

Clearance

Data regarding the clearance of niacin is not readily available.

Elimination Route

69.5% of a dose of niacin is recovered in urine. 37.9% of the recovered dose was N-methyl-2-pyridone-5-carboxamide, 16.0% was N-methylnicotinamide, 11.6% was nicotinuric acid, and 3.2% was niacin.

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

Pregnancy & Breastfeeding use

Pregnancy category X. Use is contraindicated in pregnant women.

Contraindication

Niacin is contraindicated in patients with a known hypersensitivity to Niacin or any component of this medication, significant or unexplained hepatic dysfunction, active peptic ulcer disease or arterial bleeding.

Simvastatin should not be used in-

• Active liver disease
• Pregnant and breast feeding mother
• Women of child bearing age unless they have been adequately protected by contraception
• Hypersensitivity to any component of the preparation
• Patients with the homozygous familial hypercholesterolemia who have a complete absence of LDL receptors

Special Warning

Renal Impairment:

• Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling (combination has not been studied); use with caution. Also see individual agents.
• Severe renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (combination has not been studied). Use with extreme caution or avoid unless patient already tolerating simvastatin doses ≥10 mg. Also see individual agents.

Hepatic Impairment: There are no dosage adjustments provided in the manufacturer's labeling (combination has not been studied). Contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Also see individual agents.

Acute Overdose

Supportive measures should be undertaken in the event of an overdosage. Symptoms may include nausea, dizziness, itching, vomiting, upset stomach, and flushing

There are no data available on overdose. No antidote is available. General measures should be adopted and liver function should be monitored.

Storage Condition

Store at controlled room temperature of 20°C to 25°C

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