Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
Patients with Hypercholesterolemia Requiring Modifications of Lipid Profiles
Simcor
Simcor is indicated to reduce Total-C, LDL-C, Apo B, non-HDL-C, TG, or to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.
Simcor is indicated to reduce TG in patients with hypertriglyceridemia when treatment with simvastatin monotherapy or niacin extended-release monotherapy is considered inadequate.
Limitations of use
No incremental benefit of Simcor on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.
Simcor Dosage and Administration
Recommended Dosing
Simcor should be taken as a single daily dose at bedtime, with a low fat snack. Patients not currently on niacin extended-release and patients currently on niacin products other than niacin extended-release should start Simcor at a single 500/20 mg tablet daily at bedtime. Patients already taking simvastatin 20 to 40 mg who need additional management of their lipid levels may be started on a Simcor dose of 500/40 mg once daily at bedtime. [See Warnings and Precautions (5.2)]. The dose of niacin extended-release should not be increased by more than 500 mg daily every 4 weeks - see Table 1.
Table 1. Recommended niacin extended-release dosing
| |
Week(s) |
Daily dose of niacin extended-release |
| Initial Titration Schedule |
1 to 4 |
500 mg |
| |
5 to 8 |
1000 mg |
| |
* |
1500 mg |
| |
* |
2000 mg |
| * After Week 8, titrate to patient response and tolerance. If response to 1000 mg daily is inadequate, increase dose to 1500 mg daily; may subsequently increase dose to 2000 mg daily. Daily dose should not be increased more than 500 mg in a 4-week period, and doses above 2000 mg daily are not recommended. |
The recommended maintenance dose for Simcor is 1000/20 mg to 2000/40 mg (two 1000/20 mg tablets) once daily depending on patient tolerability and lipid levels. The efficacy and safety of doses of Simcor greater than 2000/40 mg daily have not been studied and are therefore not recommended.
If Simcor therapy is discontinued for an extended period of time (> 7 days), re-titration as tolerated is recommended. Simcor tablets should be taken whole and should not be broken, crushed, or chewed before swallowing.
Due to the increased risk of hepatotoxicity with other modified-release (sustained-release or time-release) niacin preparations or immediate-release (crystalline) niacin, Simcor should only be substituted for equivalent doses of niacin extended-release (NIASPAN).
Flushing [See Adverse Reactions (6.1)] may be reduced in frequency or severity by pretreatment with aspirin up to the recommended dose of 325 mg (taken approximately 30 minutes prior to Simcor dose). Flushing, pruritus, and gastrointestinal distress are also reduced by gradually increasing the dose of niacin (refer to Table 1) and avoiding administration on an empty stomach. Concomitant alcoholic, hot drinks or spicy foods may increase the side effects of flushing and pruritus and should be avoided around the time of Simcor ingestion.
Coadministration with Other Drugs
Patients taking Amlodipine or Ranolazine
- The dose of Simcor should not exceed 1000/20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.4), and Clinical Pharmacology (12.3)].
Chinese Patients Taking Simcor
Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when prescribing Simcor in doses that exceed 1000/20 mg/day to Chinese patients. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Warnings and Precautions
(5.1)].
Dosage Forms and Strengths
Simcor tablets are formulated for oral administration in the following strength combinations:
Table 2. Simcor Tablet Strengths
| |
500mg/20mg |
500mg/40mg |
750mg/20mg |
1000mg/20mg |
1000mg/40mg |
| Niacin extended-release equivalent (mg) |
500 |
500 |
750 |
1000 |
1000 |
| simvastatin equivalent (mg) |
20 |
40 |
20 |
20 |
40 |
Contraindications
Simcor is contraindicated in the following conditions:
- Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [See Warnings and Precautions (5.2)]
- Patients with active peptic ulcer disease
- Patients with arterial bleeding
- Concomitant administration of strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1) ]
- Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)]
- Concomitant administration of amiodarone, verapamil, or diltiazem [see Warnings and Precautions (5.1)]
- Women who are pregnant or may become pregnant. Simcor may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of Simcor use during pregnancy; however in rare reports congenital anomalies were observed following intrauterine exposure to HMG-CoA reductase inhibitors. If Simcor is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. [See Use In Specific Populations (8.1) ] In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. There are no animal reproductive studies conducted with niacin.
- Nursing mothers. Simcor contains simvastatin and nicotinic acid. Nicotinic acid is excreted into human milk and it is not known whether simvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because of the potential for serious adverse reactions in nursing infants, women who require Simcor treatment should not breastfeed their infants. [See Use In Specific Populations (8.3)]
- Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including one of more of the following adverse reactions have been reported for simvastatin and/or niacin extended-release: anaphylaxis, angioedema, urticaria, fever, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and flushing. [See Adverse Reactions (6.1)]
Warnings and Precautions
Simcor should not be substituted for equivalent doses of immediate-release (crystalline) niacin. For patients switching from immediate-release niacin to Simcor, therapy with Simcor should be initiated at 500/20 mg and appropriately titrated to the desired therapeutic response. Patients already taking simvastatin 20-40 mg who need additional management of their lipid levels may be started on a Simcor dose of 500/40 mg once daily at bedtime. Doses of Simcor greater than 2000/40 mg are not recommended.
Myopathy/Rhabdomyolysis
Simvastatin
Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.
The risk of myopathy/rhabdomyolysis is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin with 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with ZOCOR (mean follow-up 6.7 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]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day; the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was approximately 0.4% in patients on 80 mg/day compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.
All patients starting therapy with Simcor, or whose dose of Simcor is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report symptoms promptly. Simcor therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.
Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with Simcor should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes.
Drug Interactions
The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily), and combination of these drugs with Simcor is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Simcor must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1) ].In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the Simcor dose may be needed to reduce the risk of myopathy/rhabdomyolysis if voriconazole must be used concomitantly with simvastatin. [see Drug Interactions (7.1)].
The combined use of Simcor with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1)].
The combined use of Simcor with amiodarone, verapamil, or diltiazem is contraindicated, because dosages of simvastatin are not to exceed 10 mg when these drugs are co-administered and all doses of Simcor contain simvastatin in excess of 10 mg. [See Contraindications (4) and Drug Interactions (7.2) ].
The combined use of Simcor with drugs that cause myopathy/rhabdomyolysis when given alone, such as fibrates, should be avoided [See Drug Interactions (7.3)].
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing Simcor with colchicine [see Drug Interactions (7.8)].
The benefits of the combined use of Simcor with amlodipine or ranolazine should be carefully weighed against the potential risks of combination. [See Drug Interactions (7.4)]. Periodic CK determinations may be considered in patients starting therapy with or increasing the dose of these agents, but there is no assurance that such monitoring will prevent myopathy.
Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid modifying doses of a niacin-containing product. Caution should be used when prescribing Simcor in doses that exceed 1000/20 mg/day to Chinese patients. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Dosage and Administration(2.3)].
Prescribing recommendations for interacting agents are summarized in Table 3 [see also Dosage and Administration (2.2), Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].
TABLE 3
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis |
| Interacting Agents |
Prescribing Recommendations |
Itraconazole
Ketoconazole
Posaconazole
Erythromycin
Clarithromycin
Telithromycin
HIV protease inhibitors
Nefazodone
Gemfibrozil
Cyclosporine
Danazol
Amiodarone
Verapamil
Diltiazem |
Contraindicated with Simcor |
Amlodipine
Ranolazine
|
Do not exceed 1000/20 mg Simcor daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
Simcor
Myopathy and/or rhabdomyolysis have been reported when simvastatin is used in combination with lipid-altering doses (≥ 1 gram/day) of niacin. Physicians contemplating the use of Simcor, a combination of simvastatin and niacin extended-release (NIASPAN), should weigh the potential benefits and risks, and should carefully monitor for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial month of treatment or during any period of upward dosage titration of either drug. Periodic determination of serum creatine kinase (CK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent myopathy.
Patients starting therapy with Simcor should be advised of the risk of myopathy, and told to report promptly unexplained muscle pain, tenderness, or weakness. A CK level above ten times the upper limit of normal (ULN) in a patient with unexplained muscle symptoms indicates myopathy. Simcor therapy should be discontinued if myopathy is diagnosed or suspected.
In patients with complicated medical histories predisposing to rhabdomyolysis, such as renal insufficiency, dose escalation requires caution. Also, as there are no known adverse consequences of brief interruption of therapy, treatment with Simcor should be stopped for a few days before elective major surgery and when any major acute medical or surgical condition supervenes (e.g., sepsis, hypotension, dehydration, major surgery, trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures).
Liver Dysfunction
Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release (modified-release, timed-release) niacin products for immediate-release (crystalline) niacin at equivalent doses. Patients previously receiving niacin products other than niacin extended-release (NIASPAN) should be started on Simcor at the lowest recommended starting dose. [See Dosage and Administration (2)]
Simcor should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of Simcor. [See Contraindications (4)]
Niacin extended-release (NIASPAN) and simvastatin can cause abnormal liver tests. In a simvastatin-controlled, 24 week study with Simcor in 641 patients, there were no persistent increases (to more than 3x the ULN) in serum transaminases. In three placebo-controlled clinical studies of niacin extended-release, patients with normal serum transaminases levels at baseline did not experience any transaminase elevations greater than 3x the ULN. Persistent increases (to more than 3x the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminases levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.
Liver function tests should be performed on all patients during therapy with Simcor. It is recommended that liver function tests be performed before treatment begins, every 12 weeks for the first 6 months, and periodically thereafter (e.g., at approximately 6-month intervals). Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality returns to normal. Should an increase in transaminase levels of more than 3x ULN persist, or if transaminase elevations are associated with symptoms of nausea, fever, and/or malaise, withdrawal of Simcor therapy is recommended. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1) ].
Laboratory Abnormalities
Increase in Blood Glucose: Niacin treatment can increase fasting blood glucose. In a simvastatin-controlled, 24-week study with Simcor the change from baseline in glycosylated hemoglobin levels was 0.2% for Simcor-treated patients and 0.2% for simvastatin-treated patients. Diabetic or potentially diabetic patients should be observed closely during treatment with Simcor, particularly during the first few months of therapy. Adjustment of diet and/or hypoglycemic therapy or discontinuation of Simcor may be necessary.
Reduction in platelet count: Niacin can reduce platelet count. In a simvastatin-controlled, 24-week study with Simcor the mean percent change from baseline for patients treated with 2000/40 mg daily was -5.6%.
Increase in ProthrombinTime (PT): Niacin can cause small increases in PT . In a simvastatin-controlled, 24-week study with Simcor this effect was not seen.
Increase in Uric Acid: Elevated uric acid levels have occurred with niacin therapy. In a simvastatin-controlled, 24-week study with Simcor this effect was not seen. Nevertheless, in patients predisposed to gout, Simcor therapy should be used with caution.
Decrease in Phosphorus: Small dose-related reductions in phosphorous levels were seen in clinical studies with niacin. In a simvastatin-controlled, 24-week study with Simcor this effect was not seen.
Adverse Reactions
Overview
In a controlled clinical study, 14% of patients randomized to Simcor discontinued therapy due to an adverse event. Flushing episodes (i.e., warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse reactions, occurring in up to 59% of patients treated with Simcor. Spontaneous reports with niacin extended-release and clinical studies of Simcor suggest that flushing may be accompanied by symptoms of dizziness or syncope, tachycardia, palpitations, shortness of breath, sweating, burning sensation/skin burning sensation, chills, and/or edema.
Clinical Studies Experience
Simcor
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The safety data described below reflect exposure to Simcor in 403 patients in a controlled study for a period of 6 months.
Flushing: Flushing (warmth, redness, itching and/or tingling) occurred in up to 59% of patients treated with Simcor. Flushing resulted in study discontinuation for 6.0% of patients.
More Common Adverse Reactions: In addition to flushing, adverse reactions occurring in ≥ 3% of patients (irrespective of investigator causality) treated with Simcor are shown in Table 4 below:
Table 4 Adverse Reactions Occurring in ≥ 3% of Patients in a Controlled Clinical Trial
| Adverse Event |
Simcor overall * |
Simvastatin overall ** |
| Total Number of Patients |
N=403 |
N=238 |
Headache |
18 (4.5%) |
11 (4.6%) |
Pruritus |
13 (3.2%) |
0 (0.0%) |
Nausea |
13 (3.2%) |
10 (4.2%) |
Back Pain |
13 (3.2%) |
5 (2.1%) |
Diarrhea |
12 (3.0%) |
7 (2.9%) |
* Simcor overall included all doses from 500/20 mg to 2000/40 mg
** Simvastatin overall included 20 mg, 40 mg, and 80 mg doses |
Simvastatin
In pre-marketing controlled clinical studies and their open extensions (2,423 patients with mean duration of follow-up of approximately 18 months) 1.4% of patients discontinued due to adverse reactions. The most commonly reported adverse reactions (incidence > 1%) in simvastatin controlled clinical trials were: headache (3.5%), abdominal pain (3.5%), constipation (2.3%), upper respiratory infection (2.1%), diarrhea (1.9%), and flatulence (1.9%).
Other Clinical Studies
In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 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]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment.
Niacin Extended-Release
In placebo-controlled clinical trials (n=245), flushing episodes were the most common treatment-emergent adverse events (up to 88% of patients) for niacin extended-release. Other adverse events occurring in 5% or greater of patients treated with niacin extended-release are headache (9%), diarrhea (7%), nausea (5%), rhinitis (5%), and dyspepsia (4%) at a maintenance dose of 1000mg daily.
Clinical Laboratory Abnormalities:
Simcor
Chemistry
Elevations in serum transaminases [See Warnings and Precautions (5.2)], CK, fasting glucose, uric acid, alkaline phosphatase, LDH, amylase, γ-glutamyl transpeptidase, bilirubin, and reductions in phosphorus, and abnormal thyroid function tests.
Hematology
Reductions in platelet counts and prolongation of PT. [See Warnings and Precautions (5.3)]
Postmarketing Experience
See also the full prescribing information for niacin extended release (Niaspan) and simvastatin products.
Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Simvastatin
The following additional adverse reactions have been identified during postapproval use of simvastatin. Hypersensitivity reaction including one 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; 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 (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), muscle cramps, vomiting, malaise.
NIASPAN
The following additional adverse reactions have been identified during post-approval use of NIASPAN. Hypersensitivity reaction including one or more of the following features: anaphylaxis, dyspnea, angioedema, tongue edema, larynx edema, face edema, laryngismus; tachycardia, atrial fibrillation, other cardiac arrhythmias, palpitations, hypotension, postural hypotension, dizziness, syncope, flushing, burning sensation/skin burning sensation, paresthesia, urticaria, vesiculobullous rash, maculopapular rash, sweating, dry skin, skin discoloration, blurred vision, macular edema, myalgia, myopathy, peptic ulcers, eructation, flatulence, hepatitis, jaundice, peripheral edema, asthenia, nervousness, insomnia, migraine, gout, and decreased glucose tolerance.
Drug Interactions
No drug interaction studies were conducted with Simcor. However, the following interactions have been noted with the individual components of Simcor:
Simvastatin
Strong CYP3A4 Inhibitors, cyclosporine, or danazol
Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.
Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of Simcor. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Simcor must be suspended during the course of treatment.
Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of Simcor be considered during concomitant use of voriconazole and Simcor to reduce the risk of myopathy, including rhabdomyolysis. [see Warnings and Precautions (5.1).]
Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
Amiodarone, Verapamil, or Diltiazem
The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of amiodarone, verapamil, or diltiazem with doses of simvastatin exceeding 10 mg. Because all doses of Simcor contain simvastatin in excess of 10 mg, concomitant use of these drugs is contraindicated.[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]
Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
Gemfibrozil: Contraindicated with Simcor [see Contraindications (4) and Warnings and Precautions (5.1)]. Other fibrates: Combined use with Simcor should be avoided. [see Warnings and Precautions (5.1).]
Amlodipine or Ranolazine
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amlodipine or ranolazine [see Dosage and Administration (2.2) and Warnings and Precautions (5.1)and Table 3 inClinical Pharmacology (12.3)].
Propranolol
In healthy male volunteers there was a significant decrease in mean Cmax, but no change in AUC, for simvastatin total and active inhibitors with concomitant administration of single doses of simvastatin and propranolol. The clinical relevance of this finding is unclear. The pharmacokinetics of the enantiomers of propranolol were not affected.
Digoxin
Concomitant administration of a single dose of digoxin in healthy male volunteers receiving simvastatin resulted in a slight elevation (less than 0.3 ng/mL) in digoxin concentrations in plasma (as measured by a radioimmunoassay) compared to concomitant administration of placebo and digoxin. Patients taking digoxin should be monitored appropriately when Simcor is initiated.
Coumarin Anticoagulants
In normal volunteers and hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants since the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteers and patients, respectively. With other reductase inhibitors, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting Simcor and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of Simcor is changed or discontinued, the same procedure should be repeated.
Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing Simcor with colchicine.[see Warnings and Precautions (5.1)
Niacin
Aspirin
Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.
Antihypertensive Therapy
Niacin may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension.
Bile Acid Sequestrants
An in vitro study was carried out investigating the niacin-binding capacity of colestipol and cholestyramine. 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 Simcor.
Other
Nutritional supplements containing large doses of niacin or related compounds may potentiate the adverse effects of Simcor.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category X – [See Contraindications (4)]
Simcor is contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of Simcor use during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to HMG-CoA reductase inhibitors in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Simcor may cause fetal harm when administered to a pregnant woman. If Simcor is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Simcor contains simvastatin (a HMG-CoA reductase inhibitor) and niacin (nicotinic acid). There are rare reports of congenital anomalies following intrauterine exposure to HMG-CoA reductase inhibitors. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. It is not known whether niacin at doses used for lipid disorders can cause fetal harm when administered to a pregnant woman.
Simvastatin was not teratogenic in rats or rabbits at doses that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice. Animal reproduction studies have not been conducted with niacin.
Women of childbearing potential, who require Simcor treatment for a lipid disorder, should use effective contraception. Patients trying to conceive should contact their prescriber to discuss stopping Simcor treatment. If pregnancy occurs, Simcor should be immediately discontinued.
Nursing Mothers
It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Niacin is excreted into human milk but the actual infant dose or infant dose as a percent of the maternal dose is not known. Because of the potential for serious adverse reactions in nursing infants, nursing mothers who require Simcor treatment should not breastfeed their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother. [see Contraindications (4)].
Pediatric Use
The safety and effectiveness of Simcor in pediatric patients have not been established.
Geriatric Use
There were 281 (30.8%) patients aged 65 years and older treated with Simcor in Phase III clinical studies. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Simcor should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Gender
Data from the clinical trials suggest that women have a greater hypolipidemic response than men at equivalent doses of niacin extended-release. No consistent gender differences in efficacy and safety were observed in Simcor studies.
Renal Impairment
No pharmacokinetic studies have been conducted in patients with renal impairment for Simcor. Caution should be exercised when Simcor is administered to patients with renal disease. For patients with severe renal insufficiency, Simcor should not be started unless the patient has already tolerated treatment with simvastatin at a dose of 10 mg or higher. Caution should be exercised when Simcor is administered to these patients and they should be closely monitored.
Hepatic Impairment
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for Simcor. [See Warnings and Precautions (5.2).]
Overdosage
Supportive measures should be taken in the event of an overdose. The dialyzability of niacin, or of simvastatin and its metabolites, is not known.
A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae.
Simcor Description
Simcor tablets contain niacin extended-release (NIASPAN) and simvastatin in combination. Simvastatin, an inhibitor of HMG-CoA reductase, and niacin are both lipid-altering agents.
Niacin Extended-Release
Niacin is nicotinic acid, or 3-pyridinecarboxylic acid. Niacin is a white, nonhygroscopic crystalline powder that is very soluble in water, boiling ethanol, and propylene glycol. It is insoluble in ethyl ether. The empirical formula of niacin is C6H5NO2 and its molecular weight is 123.11. Niacin has the following structural formula:
Simvastatin
Simvastatin is butanoic acid, 2,2 - dimethyl - ,1,2,3,7,8,8a - hexahydro - 3 - 7 - dimethyl - 8 - [2 - (tetrahydro - 4 - hydroxy - 6 - oxo - 2H - pyran - 2 - yl) - ethyl] - 1 - naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*4S*),-8aβ]]. Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol, and ethanol. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. Simvastatin has the following structural formula:
Simcor is available for oral administration as tablets containing 500 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor 500/20 mg), 500 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (Simcor 500/40 mg), 750 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor 750/20 mg), 1000 mg of niacin extended-release (NIASPAN) and 20 mg simvastatin (Simcor 1000/20 mg) and 1000 mg of niacin extended-release (NIASPAN) and 40 mg simvastatin (Simcor 1000/40 mg). Each tablet contains the following inactive ingredients: hypromellose, povidone, stearic acid, polyethylene glycol, butylated hydroxyanisole, FD&C Blue #2, lactose monohydrate, titanium dioxide, triacetin. Simcor 500/20 mg, Simcor 750/20 mg, and Simcor 1000/20 mg also contain iron oxide.
Simcor - Clinical Pharmacology
Mechanism of Action
Niacin
Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. The mechanism by which niacin alters lipid profiles is not completely understood and may involve several actions, including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity (which may increase the rate of chylomicron triglyceride removal from plasma). Niacin decreases the rate of hepatic synthesis of VLDL-C and LDL-C, and does not appear to affect fecal excretion of fats, sterols, or bile acids.
Simvastatin
Simvastatin is a prodrug and is hydrolyzed to its active ß-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.
Pharmacodynamics
A variety of clinical studies have demonstrated that elevated levels of Total-C, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C, and inversely with the level of HDL-C.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermedi
