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, 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 3 below:

Table 3: Adverse Reactions Occurring in ≥ ; 3% of Patients in a Controlled Clinical Trial

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%).

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], 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].

Postmarketing Experience

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.

NIASPAN

The following additional adverse reactions have been identified during postapproval use of NIASPAN. Hypersensitivity reaction including one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, vesiculobullous rash, palpitations, syncope, hypotension, orthostasis, decreased glucose tolerance, gout, hepatitis, skin discoloration, rhabdomyolysis, amblyopia, and insomnia.

No drug interaction studies were conducted with SIMCOR. However, the following interactions have been noted with the individual components of SIMCOR:

Simvastatin

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.

Potent inhibitors of CYP3A4 include:

Itraconazole, ketoconazole, and other antifungal azoles,

Macrolide antibiotics erythromycin, clarithromycin, and telithromycin,

HIV protease inhibitors,

Antidepressant nefazodone,

Grapefruit juice in large quantities ( > 1 quart daily).

Potent inhibitors of CYP3A4 increase the risk of myopathy by reducing the elimination of simvastatin. Hence when simvastatin is used with a potent inhibitor of CYP3A4, elevated plasma levels of HMG- CoA reductase inhibitory activity can increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See WARNINGS and PRECAUTIONS]

Serious skeletal muscle disorder, e.g., rhabdomyolysis, have been reported during concomitant therapy of simvastatin or other HMG-CoA reductase inhibitors with cyclosporine, danazol, itraconazole, ketoconazole, gemfibrozil, niacin, erythromycin, clarithromycin, telithromycin, nefazodone or HIV protease inhibitors.

Concomitant use of drugs labeled as potent inhibitors of CYP3A4 should be avoided unless the benefits of combined therapy outweigh the increased risk. If treatment with itraconazole, ketoconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with SIMCOR should be suspended during the course of treatment.

Cyclosporine or Danazol

Although the mechanism is not fully understood, cyclosporine has been shown to increase the area under the curve (AUC) of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy/rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol particularly with higher doses of simvastatin. [See WARNINGS and PRECAUTIONS]

Amiodarone or Verapamil

The risk of myopathy/rhabdomyolysis is increased by concomitant administration of amiodarone or verapamil with higher doses of simvastatin. [SeeWARNINGS and PRECAUTIONS]

Gemfibrozil and other Fibrates

Coadministration of gemfibrozil (600 mg twice daily for 3 days) with simvastatin (40 mg daily) resulted in clinically significant increases in simvastatin acid AUC (185%) and peak plasma concentration (Cmax,112%), possibly due to inhibition of simvastatin acid glucuronidation by gemfibrozil. The increase in simvastatin exposure increases the risk of myopathy when coadministred with gemfibrozil. The combined use of SIMCOR with gemfibrozil should be avoided [See WARNINGS and PRECAUTIONS]. The risk of myopathy also increases to a lesser extent when simvastatin is used in combination with other fibrates. Coadministration of 160 mg fenofibrate daily with 80 mg simvastatin daily for 7 days had no effect on plasma AUC (and Cmax) of either total HMG-CoA reductase inhibitory activity or fenofibric acid; there was a modest reduction (approximately 35%) of simvastatin acid which was not considered clinically significant.

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.

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.

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