"June 9, 2011 -- The FDA today tightened its rules on who should take the highest approved dose of the statin drug simvastatin.
Simvastatin, which lowers LDL "bad" cholesterol, is sold under the brand name Zocor and as a generic drug. "...
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
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
** Simvastatin overall included 20 mg, 40 mg, and 80 mg doses
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides
Impact on Global Health Outcomes (AIM-HIGH)
In AIM-HIGH involving 3414 patients (mean age of 64 years, 15% women, 92% Caucasians, 34% with diabetes mellitus) with stable, previously diagnosed cardiovascular disease, all patients received simvastatin, 40 to 80 mg per day, plus ezetimibe 10 mg per day if needed, to maintain an LDL-C level of 40-80 mg/dL, and were randomized to receive NIASPAN 1500-2000 mg/day (n=1718) or matching placebo (IR Niacin, 100-150 mg, n=1696). The incidence of the adverse reactions of “blood glucose increased” (6.4% vs. 4.5%) and “diabetes mellitus” (3.6% vs. 2.2%) was significantly higher in the simvastatin plus NIASPAN group as compared to the simvastatin plus placebo group. There were 5 cases of rhabdomyolysis reported, 4 (0.2%) in the simvastatin plus NIASPAN group and one ( < 0.1%) in the simvastatin plus placebo group [see WARNINGS AND PRECAUTIONS].
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.
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
Elevations in serum transaminases [see WARNINGS AND PRECAUTIONS], CK, fasting glucose, uric acid, alkaline phosphatase, LDH, amylase, γ-glutamyl transpeptidase, bilirubin, and reductions in phosphorus, and abnormal thyroid function tests.
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.
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, fatal and nonfatal hepatic failure, pruritus, cataracts, polymyositis, dermatomyositis, polymyalgia rheumatica, tendon rupture, peripheral neuropathy, 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.
There have been rare reports of immune-mediated necrotizing myopathy with statin use [see WARNINGS AND PRECAUTIONS].
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
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.
Read the Simcor (simvastatin niacin extended release) Side Effects Center for a complete guide to possible side effects
No drug interaction studies were conducted with SIMCOR. However, the following interactions have been noted with the individual components of SIMCOR:
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 and CLINICAL PHARMACOLOGY]. Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see CONTRAINDICATIONS]. 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].
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, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Verapamil or Diltiazem
The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
Amlodipine or Ranolazine
The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amlodipine or ranolazine [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS and Table 5 in CLINICAL PHARMACOLOGY].
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.
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.
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.
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].
Concomitant use of aspirin may decrease the metabolic clearance of niacin. The clinical relevance of this finding is unclear.
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.
Nutritional supplements containing large doses of niacin or related compounds may potentiate the adverse effects of SIMCOR.
Read the Simcor Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/7/2013
This monograph has been modified to include the generic and brand name in many instances.
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