Dosing and uses of Advicor (lovastatin-niacin)
Hypercholesterolemia & Mixed Dyslipidemia
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tablets for coadministration with statins no longer outweigh the risks, and the approval for this indication should be withdrawn
Pediatric dosage forms and strengths
Not recommended
Advicor (lovastatin-niacin) adverse (side) effects
Frequency not defined
CPK elevation
Muscle cramp
Myalgia
Myopathy
Rhabdomyolysis
Increased LFTs
Hepatotoxicity
Hyperglycemia
Abdominal pain
Constipation
Diarrhea
Flatulence
GI upset
Nausea/vomiting
Dizziness
Headache
Weakness
Facial flushing
Pruritus
Warnings
Contraindications
Hypersensitivity to lovastatin or niacin
Active liver disease, or unexplained elevated transminases, active PUD, arterial bleeding
Concomitant administration of lovastatin with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, cobicistat, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone)
Pregnancy, lactation
Cautions
Avoid concomitant use with anticoagulants, or dilators, grapefruit juice (>1 quart/day)
Heavy alcohol use, history of liver disease , renal failure, DM, gout, unstable angina
Withhold or discontinue if myopathy develops, renal failure, or transaminase levels >3x ULn
Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin
Rhabdomyolysis risk and myopathy increased by coadministration of lovastatin with CYP3A4 inhibitors or other drugs (eg, fibrates, high-dose niacin, cyclosporine) that cause myopathy (see Contraindications)
Avoid coadministration of lovastatin with cyclosporine or gemfibrozil; caution with other fibrates or lipid-lowering doses of niacin (≥1 g/day) because of increased risk for myopathy
Pregnancy and lactation
Pregnancy category: X
Lactation: Contraindicated
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.
Pharmacology of Advicor (lovastatin-niacin)
Mechanism of action
Lovastatin: HMG-CoA reductase inhibitor, inhibits the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
Niacin: Component of 2 coenzymes necessary for tissue respiration, glycogenolysis, and lipid metabolism; inhibits synthesis of low density lipoproteins
Pharmacokinetics
Lovastatin
- Onset: 3 days (reduction of LDL cholesterol); maximum response 4-6 weeks
- Bioavailability: >30% with extended release formulation when taken in fasting state
- Protein binding: >95%
- Metabolism: Extensive hepatic metabolism; hydrolyzed to β-hydroxyacid (active metabolism)
- Half-life: 1.1-1.7 hr
- Peak plasma time: 2-4 hr (immediate release); 12-14 hr (extended release)
- Excretion: Urine (10%); feces (80-85%)
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 simvastatin 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 (https://optiviabio.com/index.html)
Administration
Instructions
Take with cold liquid
Take with food (low fat snack); do not take on empty stomach
Monitor LFT 6 weeks after initiation or dose escalation
Pretreatment with nonenteric coated aspirin may reduce flushing
If therapy interrupted >7 days reinstitution of therapy may begin by intitiating therapy at lowest dose and slow titration as needed
