simvastatin/niacin (Discontinued)

Brand and Other Names:Simcor
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Dosing & Uses

AdultPediatric

Hyperlipidemia

December 31, 2015: Manufacturer voluntarily withdrew drug from the market and discontinued distribution

April 15, 2016: Based on several large cardiovascular outcome trials including AIM-HIGH, ACCORD, and HPS2-THRIVE, the FDA decided that "scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL-cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events"

Consistent with this conclusion, the FDA has determined that the benefits of niacin ER tablets for coadministration with statins no longer outweigh the risks, and the approval for this indication should be withdrawn

Safety and efficacy not established

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Interactions

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and simvastatin/niacin

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            Adverse Effects

            >10%

            Flushing (up to 59%)

            1-10%

            Headache (4.5%)

            Backache (3.2%)

            Nausea (3.2%)

            Pruritus (3.2%)

            Diarrhea (3%)

            Frequency Not Defined

            CPK increased

            Rhabdomyolysis

            LFT's increased

            Postmarketing Reports

            Hypersensitivity reaction including 1 or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, vasculitis, purpura, thrombocytopenia, leucopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, photosensitivity, chills, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, fever, dyspnea, and arthralgia

            Other: pancreatitis, hepatitis, hepatic failure, pruritus, cataracts, polymyositis, dermatomyositis, polymyalgia rheumatica, global amnesia, tendon rupture, peripheral neuropathy, memory impairment, erectile dysfunction, depression, interstitial lung disease, alopecia, a variety of skin changes (eg, nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), muscle cramps, vomiting, and malaise

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            Warnings

            Contraindications

            Hypersensitivity

            Active liver disease or unexplained elevated transaminases

            Active peptic ulcer, arterial bleeding

            Pregnancy, lactation

            Strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, boceprevir, telaprevir, cobicistat) or other drugs that may increase systemic simvastatin exposure (eg, gemfibrozil, cyclosporine, danazol, amiodarone, verapamil, diltiazem)

            Cautions

            Increase dose gradually and avoid taking on empty stomach to reduce flushing, pruritus, and GI distress from niacin

            Severe renal disease

            Increased HbA1c and fasting serum glucose levels reported with simvastatin

            Simvastatin and myopathy risk

            • Dose adjustment required when coadministered with amlodipine or ranolazine
            • Grapefruit juice may increase simvastatin serum levels and increase risk for myopathy/rhabdomyolysis; avoid large quantities of grapefruit juice (>1 quart/day)
            • See Contraindications for list of drugs contraindicated because of increased risk for myopathy when coadministered with simvastatin
            • Predisposing factors for myopathy include advanced age (&ge65 years), female gender, uncontrolled hypothyroidism, and renal impairment
            • Increased risk for myopathy in Chinese patients coadministered niacin >1 g/day
            • Withhold or discontinue if myopathy, renal failure, or transaminase levels >3x ULN develop
            • Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin
            • See Adult Dosing for dose limitations
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            Pregnancy & Lactation

            Pregnancy Category: X

            Lactation: do not take if nursing

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Simvastatin: HMG-CoA reductase inhibitor, inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase

            Niacin: Component of two coenzymes necessary for lipid metabolism, tissue respiration, glycogenolysis, inhibits VLDL synthesis

            Pharmacokinetics

            Simvastatin

            • Onset: >3 days; 2 weeks (peak effect)
            • Bioavailability: <5%
            • Protein binding: 95%
            • Peak plasma time: 1.3-2.4 hr
            • Excretion: Feces (60%); urine (13%)

            Niacin

            • Bioavailability: 60-76% (absorption rapid, extensive)
            • Half-life: 20-45 min
            • Peak plasma time: 30-60 min (immediate release); 4-5 hr (extended release formulation)
            • Excretion: Urine (60-88%)
            • Protein binding: 20%
            • Distribution: Hepatic, renal and adipose tissue distribution
            • Metabolism: First pass effect; conversted to nicotinamide adenine dinucleotide (NAD-active metabolite), [nicotinamide, nicotinuric acid] (inactive)

            Pharmacogenomics

            SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

            This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

            SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, pravastatin, simvastatin)

            Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

            SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

            Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes

            Genetic testing laboratories

            • Optivia Biotechnology, Inc (http://optiviabio.com/index.html)
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            Administration

            Instructions

            Take with cold liquid and a lowfat snack

            Swallow tablet whole; do not break, crush, or chew

            Flushing may be reduced by pre-treatment with non enteric-coated aspirin or NSAIDs, 30 minutes before dose

            Retitrate dose if therapy discontinued for >7 days

            Due to risk of hepatotoxicity, substitute Simcor only for equivalent doses of niacin-ER, and not other forms of niacin

            Monitor LFTs 6 weeks after initiation or dose escalation

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