nla safety task force report: the nonstatins

© 2006 National Lipid Association

NLA Safety Task Force Report: The Nonstatins

March 19, 2007


The NLA Safety Task ForceJames M. McKenney, PharmD, Chairman Virginia Commonwealth UniversityRichmond, Virginia

Harold E. Bays, MD Louisville Metabolic and Atherosclerosis Research CenterLouisville, Kentucky

Michael H. Davidson, MDRush University Medical CenterChicago, Illinois

John R. Guyton, MDDuke University Medical CenterDurham, North Carolina

Terry A. Jacobson, MDEmory UniversityAtlanta, Georgia


Task Force Mission• Conduct a comprehensive, rigorous,

scholarly, up-to-date, and unbiased assessment of the safety of lipid-altering therapies.

• Use the findings from this assessment to educate health professionals on how to help patients lower their cholesterol and reduce their risk of heart attacks and strokes.


Safety Considerations with Fibrate Therapy

March 19, 2007

Michael H. Davidson, MDAnnemarie Armani, MDJames M. McKenney, PharmDTerry A. Jacobson, MD


Recommendations to healthcare professionals regarding fibrate safety

1. Before the initiation of fibrate therapy, a measurement of serum creatinine should be determined. If impaired renal function is present, the patient should be prescribed gemfibrozil (unless taking a statin), or a lower starting dose of fenofibrate (48 mg is most commonly available) should be considered. With impaired renal function, the periodic monitoring of renal function is recommended.

2. Routine monitoring of creatinine is not required, but if a patient has a clinically important increase in creatinine, and other potential causes of creatinine increase have been excluded, consideration should be given to discontinuing fibrate therapy or reducing the dose.

3. Creatinine monitoring may be advisable if a patient is taking another medication, such as metformin, which may need to be discontinued for creatinine elevations 1.4 mg/dL in women and 1.5 mg/dL in men, or a statin, which may require downward dosage adjustment.

CK creatine kinase; HDL high-density lipoprotein; INR international normalized ratio; IV intravenous; PT prothrombin time; ULN upper limit of normal



4. Although package inserts generally suggest using the combination of a fibrate and a statin very carefully or not at all, there are several circumstances in which the benefits may outweigh the risks. In these circumstances, fenofibrate is the preferred fibrate over gemfibrozil but still may increase the risk for myopathy or rhabdomyolysis. It is generally recommended to get a baseline CK level before adding the second lipid-lowering agent and to use the lowest dose of a statin or fibrate when possible.

5. Clinicians should still use caution when prescribing the highest doses of statins used in combination with fibrate therapy, because both classes of drugs are independently associated with an increased risk for myopathy. In combination with a statin, fenofibrate is the preferred option, and gemfibrozil should be avoided unless the clinical benefits outweigh the increased risk for myopathy. Clinicians should be aware of the maximal statin dose allowed in combination with gemfibrozil in the package insert.



6. Gemfibrozil has less effect than fenofibrate on creatinine and therefore is the National Kidney Foundation’s (NKF) fibrate of choice for renal insufficiency. It does seem reasonable to discourage the administration of fenofibrate to kidney transplant patients and those on dialysis, because fenofibrate is nondialysable.

7. In patients with renal dysfunction receiving statin therapy, especially statins with significant renal clearance (ie, simvastatin, rosuvastatin, pravastatin, and lovastatin), combination therapy with gemfibrozil should be avoided, and combination therapy with fenofibrate should be initiated with caution, if at all. The dose of fenofibrate should not exceed 48 mg (unless the benefits markedly outweigh the increased risk for rhabdomyolysis), and the statin doses should remain below the maximal levels.

8. Clinicians should warn patients about the possibility of myopathy on fibrate therapy and advise the reporting of side effects of diffuse muscle pain or weakness as soon as possible.



9. Obtaining a pretreatment baseline CK level may be considered in patients who are at high risk for experiencing muscle toxicity, but this is not routinely necessary in other patients.

10. It is not necessary to measure CK levels in asymptomatic patients during the course of fibrate therapy, because marked, clinically important CK elevations are relatively rare. CK measurements should be obtained in symptomatic patients to help gauge the severity of muscle damage and facilitate a decision of whether to continue therapy or alter doses.

11. In patients who develop intolerable muscle symptoms with or without CK elevations, and in whom other causes have been ruled out, fibrates should be discontinued. In patients who develop rhabdomyolysis (CK 10,000 IU/L or CK 10 ULN with an elevation in serum creatinine or requiring IV hydration therapy), fibrate therapy should be stopped. IV hydration therapy in a hospital setting should be instituted if indicated for patients experiencing rhabdomyolysis. Once recovered, the risks and benefits of fibrate therapy should be carefully monitored.



12. Clinicians should be aware that fibrates have not been demonstrated to significantly reduce total and cardiovascular mortality. On post hoc analysis, certain lipid subpopulations have been shown to have greater cardiovascular benefit (ie, elevated triglycerides and/or low HDL), but this needs to be confirmed prospectively.

13. Fibrate therapy elevates homocysteine, however, routine monitoring of plasma homocysteine levels on fibrate is not necesary unless further research ascertains that this elevation is clinically relevant.

14. Caution should be exercised when anticoagulants are given in conjunction with both fenofibrate and gemfibrozil because of the potentiation of coumarin-type anticoagulants in prolonging PT and the INR. Frequent PT and INR determinations are advisable, and coumadin doses may need to be reduced to maintain PT and the INR at the desired level to avoid bleeding complications.



15. All fibrates have the potential to increase the cholesterol saturation index and increase the risk for cholelithiasis; however, cases of gallbladder disease and cholecystectomies appear to be uncommon with gemfibrozil and fenofibrate. If cholelithiasis is suspected in a patient receiving fibrate therapy, gallbladder studies, including ultrasound, are indicated. If gallstones are found, consideration should be given to stopping fibrate treatment.

Davidson M, Armani A, McKenney JM, Jacobson T. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):3C-18C


Safety Considerations with Niacin Therapy

March 19, 2007

John R Guyton, MDHarold E. Bays, MD


Recommendations to healthcare professionals regarding niacin safety

1. Healthcare professionals may expect that 5%–10% of patients will not tolerate niacin in long-term use because of flushing. Some research clinics have been able to achieve considerably lower rates of discontinuation because of flushing. However, the casual prescription of any formulation of niacin without good patient education is unlikely to achieve a goal of 90% tolerability.

2. Skin rashes associated with niacin therapy are generally not allergic but are likely related to dermal prostaglandin release and to dry skin. Rashes sometimes respond to moisturizing creams or to the occasional use of steroid creams. However, withdrawal or dose reduction of niacin may be necessary. Exacerbation of eczema may occur, but psoriasis and most other skin disorders do not seem to be affected by niacin administration.

CK creatine kinase; ER extended release; HDL high-density lipoprotein; IR immediate release; PCP phencyclidine; SR sustained release; ULN upper limit of normal



3. Serious hepatic toxicity can occur with niacin therapy, but it is almost entirely associated with the use of slow-release formulations. IR (regular or crystalline) niacin or ER niacin generally should be used rather than SR niacin. Nevertheless, slow-release niacin in doses up to 1,000 mg twice daily can be used safely with liver function test monitoring (1) in exceptional cases in which only slow-release niacin is tolerated or (2) in clinics that have developed experience with a high-quality brand of slow-release niacin. If patients are taking concomitant statin therapy, then even mild liver toxicity from SR niacin might lead to decreased hepatic clearance of statins and potentially to serious myopathy. Therefore, in statin-treated patients, SR niacin doses should be limited to 1,500 mg total daily dose.

4. Hepatic transaminase levels should be monitored every 6–12 week during the first 6–12 month of treatment with niacin and periodically thereafter (eg, at 6-mo intervals). Withdrawal of niacin therapy or dosage reduction should be undertaken if persistent and substantial transaminase increases are found, especially if (1) they are 3 the ULN, (2) they are accompanied by elevated bilirubin or prothrombin time, or (3) they are accompanied by symptoms of nausea, malaise, or fever.



5. Isolated increases of serum bilirubin remaining 3 mg/dL, without other signs of hepatic toxicity, may represent niacin interference with specific bilirubin transport and should not necessarily lead to dosage reduction or withdrawal.

6. Unexplained increases in prothrombin time with only minor transaminase increases may rarely be a niacin side effect. Nevertheless, because of the rarity of this effect and the lack of a drug interaction with warfarin, niacin can be safely used in patients anticoagulated with warfarin.

7. Niacin is useful for the treatment of the dyslipidemia of diabetes mellitus, especially low HDL cholesterol. Minor increases (4%–5% on average) in glucose levels result from niacin-induced insulin resistance, but these increases are often clinically insignificant or readily treated. Glycemic control in diabetes should be monitored following niacin initiation or dosage increase.



8. In some patients with impaired fasting glucose or impaired glucose tolerance, especially with fasting glucose levels of 110–125 mg/dL, the possibility of inducing clinical diabetes may outweigh the cardiovascular benefit of niacin therapy. It is reasonable to defer niacin therapy while attempting to improve glycemic status with lifestyle and dietary measures, or alternatively, niacin may be administered with careful monitoring as lifestyle and dietary measures are instituted.

9. In patients who have increased risk for developing type 2 diabetes (eg, patients with familial or ethnic predisposition), but who do not have impaired fasting glucose or impaired glucose tolerance, the cardiovascular protection afforded by niacin will often outweigh the presumed increase in the risk for developing diabetes. No increase in the risk for new-onset diabetes or hyperglycemia was evident in a long-term placebo-controlled clinical trial, in which 853 men took an average dose of approximately 2,000 mg regular niacin over 5 years.



10. The onset of type 2 diabetes (multiple fasting glucose levels 125 mg/dL or postprandial glucose levels 200 mg/dL) in a patient taking niacin should prompt consideration of niacin withdrawal or dosage reduction. Niacin-associated insulin resistance is reversible. In a few cases (such as in patients with very low HDL responding well to niacin or patients with progressive atherosclerotic disease), cardiovascular benefits might be judged to outweigh the role of niacin in inducing and perpetuating the diabetic state. In any case, if diabetes is persistent and requires medication or insulin after niacin withdrawal, the reinitiation of niacin should be considered. The reinitiation of niacin likely will require no, or only minor, changes in antidiabetic therapy.

11. On the basis of almost 2 decades of clinical evidence, niacin coadministration with a statin does not potentiate statin-related myopathic reactions. Isolated case reports of myopathy, including rhabdomyolysis, with niacin-statin combination therapy appeared early after the clinical introduction of lovastatin. These cases might have been related to other drug interactions (polypharmacy) or possibly to hepatic toxicity from earlier forms of niacin with subsequent decreased hepatic extraction of statins and increased peripheral blood statin levels.



12. In patients with myopathic reactions or clinically significant myalgia (enough to limit statin doses) while taking niacin-statin combination therapy, other contributors to myopathy should be considered, such as hypothyroidism, excessive alcohol ingestion, increased physical activity, infections, polymyositis, dermatomyositis, trauma, and drug abuse (cocaine, amphetamines, heroin, or PCP). Otherwise, recommendations for the evaluation of myopathic reactions in patients on statin monotherapy should be followed (eg, the National Lipid Association [NLA] recommendations described in Am J Cardiol 2006;97[suppl]:88C–94C).

13. In patients predisposed to statin-induced myopathy, such as those with chronic kidney disease, elderly patients, or those engaging in extreme physical activity, one may consider obtaining pretreatment CK levels before the addition of niacin to an established statin regimen. The level of pretreatment CK can be used to judge whether and how frequently to monitor on-treatment CK levels.

14. Blurred vision due to cystoid macular edema or other ocular effects can be a dose-related side effect caused by niacin administration, requiring niacin withdrawal and perhaps retitration to a lower dose. This side effect is very rare when niacin doses 3,000 mg/day are used.



15. Niacin should not be used in the presence of active peptic ulcer disease, but a remote history of peptic ulcer is not a contraindication to niacin use. Gastroesophageal reflux disease is generally not affected by niacin.

16. Nausea and vomiting have occurred in association with higher doses of niacin but are very uncommon at doses up to 2,000 mg/day.

17. Palpitations and tachycardia are potential adverse experiences with niacin. In rare cases, this may relate to the increased incidence of “definite or suspected” atrial fibrillation found in a single large, randomized trial of high-dose, IR niacin, given in doses of 2–3 g/day. Theoretically, niacin may thus be relatively contraindicated in patients with paroxysmal atrial fibrillation. However, postoperative atrial fibrillation occurring after cardiothoracic surgery is not a contraindication to the subsequent clinical use of niacin. Furthermore, established atrial fibrillation is not a contraindication to niacin use, because the ventricular response rate is not affected by niacin.



18. Active gout is a relative contraindication to niacin use, because niacin (nicotinic acid) competes with uric acid for secretion by kidney tubules and raises serum uric acid levels by 5%–15%.

19. Laboratory abnormalities occurring with niacin may include small reductions in platelet count (mean 11% with ER niacin 2,000 mg) and serum phosphorus (mean 10% at the same dose). These abnormalities are not large enough to require monitoring and generally do not require dosage adjustment.

Guyton G, Bays H. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):22C-31C


Safety Considerations with Omega-3 Fatty Acid Therapy

March 19, 2007

Harold E. Bays, MD


Recommendations to healthcare professionals regarding fish oil therapy safety

● The clinical trial evidence does not support an increased bleeding risk with fish oil therapy, even when used in combination with other agents that may increase bleeding (such as aspirin and warfarin).

● It is reasonable to monitor patients treated with fish oils and anticoagulants for potential bleeding adverse experiences; however, it is unclear if more monitoring is required than what would otherwise be done with patients administered anticoagulants alone.

● Fish oils should probably be discontinued during acute bleeding episodes, such as hemorrhagic stroke.

● The decision to discontinue fish oils days before an invasive procedure at high risk for bleeding complications should be based on weighing the unproved potential increase in bleeding risk versus the potential reduction in atrial fibrillation before certain procedures, such as coronary artery bypass surgery.

CRN council for responsible nutrition; DHA docosahexaenoic acid; EPA eicosapentaenoic acid; FDA US food and drug administration; USP United States pharmacopeia



● Rigorous purification processes involved in fish oil manufacturing reduce the risk of fatty acid oxidation, hypervitaminosis, and exposure to environmental toxins.

● Clinicians and patients should be aware of the variance in the purification processes among different fish oil manufacturers.

● Because fish oil supplements are generally regarded as safe, they are not subject to FDA premarket and approval requirements.

● If a product has the “USP-Verified” mark on its label, the manufacturer has met voluntary USP standards, which include initial and ongoing determinations to ensure that (1) what is on the label is in fact in the bottle (all the listed ingredients in the declared amounts), (2) the supplement does not contain harmful levels of contaminants, (3) the supplement will break down and release ingredients in the body, and (4) the supplement has been made under current good manufacturing practices.



● Some fish oil manufacturers advertise voluntary compliance with the standards set by the CRN, which suggests that the fish oil manufacturers are adhering to a voluntary monograph developed by an association of manufacturers in the dietary supplement industry that specifies quality standards for fish oil supplements marketed in the United States.

● Claims of a fish oil supplement being “pharmaceutical grade” have little meaning regarding safety and have even less meaning with regard to efficacy, unless the fish oil preparation has been approved by the FDA as a prescription pharmaceutical.

● Prescription fish oil preparations undergo the same rigorous FDA regulatory requirements as other prescription pharmaceuticals, with regard to both efficacy and safety.



● One of the most common pitfalls in the day-to-day, clinical use of fish oil therapy is the sense among patients that all fish oil therapies are the same. Clinicians need to educate patients of the wide variance in fish oil therapies regarding efficacy, tolerability, and perhaps even safety. For example, the efficacy of fish oil therapy is most dependent on the amount of omega-3 fatty acids (such as EPA and DHA) in each capsule, not the total amount of fish oil concentrate. Thus, to achieve the same level of omega-3 fatty acid intake, patients may have to take as many as 11 capsules of some fish oil supplements to match the same amount of omega-3 fatty acid intake as 4 fish oil capsules of prescription fish oil.

Bays H. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):35C-43C


Safety Considerations with Gastrointestinally Active

Lipid-Lowering Drugs

March 19, 2007

Terry A. Jacobson, MD

Annemarie Armani, MDJames M. McKenney, PharmDJohn R. Guyton, MD


Recommendations to healthcare professionals regarding ezetimibe safetyEzetimibe and muscle safety

1. Obtaining a pretreatment baseline CK level is not routinely necessary before initiating ezetimibe therapy. It may be considered in patients who are at high risk for experiencing muscle toxicity (eg, in older individuals or when combining ezetimibe and a statin with other agents known to increase myotoxicity), but this is not routinely necessary in other patients.

2. It is not necessary to measure CK levels in asymptomatic patients during the course of ezetimibe therapy because marked, clinically important CK elevations are rare and are usually related to physical exertion or other causes. CK measurements should be obtained in symptomatic patients to help gauge the severity of muscle damage and facilitate a decision of whether to continue therapy or alter doses.

CK creatine kinase; FDA US food and drug administration; IV intravenous; NLA National Lipid Association; ULN upper limit of normal


Recommendations to healthcare professionals regarding ezetimibe safety3. Whenever muscle symptoms or an increased CK level is encountered in

a patient receiving ezetimibe therapy, health professionals should attempt to rule out other causes because these are most likely to explain the findings. Other common causes include increased physical activity, trauma, falls, accidents, seizures, shaking chills, hypothyroidism, infections, drug abuse (alcohol, cocaine, amphetamines, etc), or statin therapy. If other causes have been ruled out, ezetimibe should be discontinued. When the patient becomes asymptomatic, ezetimibe should be restarted to test the reproducibility of symptoms. The recurrence of symptoms requires consideration of other lipid-altering agents.

4. Obtaining a pretreatment baseline CK level is not routinely necessary before initiating ezetimibe therapy with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin). It may be considered in patients who are at high risk for experiencing muscle toxicity (eg, in older individuals or when combining ezetimibe and a statin with other agents known to increase myotoxicity).

5. In patients taking ezetimibe and statins who develop tolerable muscle complaints or are asymptomatic with CK elevations 10 ULN, the statin

portion of the therapy may be continued at the same or a reduced dose, and symptoms may be used as the clinical guide to stop or continue

therapy.

6. In patients taking ezetimibe and statins who develop intolerable muscle symptoms with CK elevations 10 ULN and in whom other causes have

been ruled out, the statins can be discontinued or reduced first. Once asymptomatic, the same or different statins, at the same or lower doses, can be

restarted to test the reproducibility of symptoms. The recurrence of symptoms with multiple statins and doses requires consideration of other lipidaltering

therapy.

7. A small number of cases of myopathy have been reported regardless of causality with ezetimibe monotherapy or with the addition of ezetimibe to

agents associated with increased risk for myopathy, such as statins. Physicians should tell patients to promptly report muscle pain, tenderness, or

weakness. Discontinue ezetimibe and any statin or fibrate if myopathy is diagnosed or suspected.

8. In patients taking ezetimibe and statins who develop rhabdomyolysis (CK elevation 10,000 IU/L or CK elevation 10 ULN with an elevation

in serum creatinine or requiring IV hydration therapy), both ezetimibe and the statin therapy should be stopped. IV hydration therapy in a hospital

setting should be instituted if indicated for patients experiencing rhabdomyolysis. Once recovered, the risk and benefits of statin therapy should be

carefully reconsidered.

Ezetimibe and liver safety

9. Because ezetimibe monotherapy has not been associated with a significant impact on liver enzymes, liver function tests are not required before

initiating therapy or in follow-up. However, during the routine general evaluation of patients being considered for any type of lipid-lowering

therapy, it is always advisable to obtain liver transaminase levels. If these test results are found to be abnormal, further investigation should be

performed to determine the cause of the abnormal test results.

10. Ezetimibe in combination therapy with statins produces slightly higher levels of liver transaminase levels than with statin therapy alone, but these

elevations are mild, transient, reversible, and without apparent clinical significance. The effect is considered to be due to the statins and is dose

related. The NLA’s recommendations to healthcare professionals regarding the liver and statin safety18 have been recently released and should be

referred to for the liver-associated risks associated with statin therapy.

11. The routine monitoring of liver function tests for ezetimibe in combination with a statin is not supported by the available evidence. However, until

there is a change in the FDA-approved prescribing information for statins, or for the combination of statins plus ezetimibe, transaminase levels

should be measured before starting therapy, and periodically thereafter.

12. Because of the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe is not

recommended for these patients. No dosage adjustment is necessary in patients with mild hepatic insufficiency.


Recommendations to healthcare professionals regarding ezetimibe safety5. In patients taking ezetimibe and statins who develop tolerable muscle

complaints or are asymptomatic with CK elevations 10 ULN, the statin portion of the therapy may be continued at the same or a reduced dose, and symptoms may be used as the clinical guide to stop or continue therapy.

6. In patients taking ezetimibe and statins who develop intolerable muscle symptoms with CK elevations 10 ULN and in whom other causes have been ruled out, the statins can be discontinued or reduced first. Once asymptomatic, the same or different statins, at the same or lower doses, can be restarted to test the reproducibility of symptoms. The recurrence of symptoms with multiple statins and doses requires consideration of other lipid-altering therapy.

7. A small number of cases of myopathy have been reported regardless of causality with ezetimibe monotherapy or with the addition of ezetimibe to agents associated with increased risk for myopathy, such as statins. Physicians should tell patients to promptly report muscle pain, tenderness, or weakness. Discontinue ezetimibe and any statin or fibrate if myopathy is diagnosed or suspected.


Recommendations to healthcare professionals regarding ezetimibe safety8. In patients taking ezetimibe and statins who develop rhabdomyolysis

(CK elevation 10,000 IU/L or CK elevation 10 ULN with an elevation in serum creatinine or requiring IV hydration therapy), both ezetimibe and the statin therapy should be stopped. IV hydration therapy in a hospital setting should be instituted if indicated for patients experiencing rhabdomyolysis. Once recovered, the risk and benefits of statin therapy should be carefully reconsidered.

Ezetimibe and liver safety

9. Because ezetimibe monotherapy has not been associated with a significant impact on liver enzymes, liver function tests are not required before initiating therapy or in follow-up. However, during the routine general evaluation of patients being considered for any type of lipid-lowering therapy, it is always advisable to obtain liver transaminase levels. If these test results are found to be abnormal, further investigation should be performed to determine the cause of the abnormal test results.


Recommendations to healthcare professionals regarding ezetimibe safety10. Ezetimibe in combination therapy with statins produces slightly higher

levels of liver transaminase levels than with statin therapy alone, but these elevations are mild, transient, reversible, and without apparent clinical significance. The effect is considered to be due to the statins and is dose related.

11. The routine monitoring of liver function tests for ezetimibe in combination with a statin is not supported by the available evidence. However, until there is a change in the FDA-approved prescribing information for statins, or for the combination of statins plus ezetimibe, transaminase levels should be measured before starting therapy, and periodically thereafter.

12. Because of the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe is not recommended for these patients. No dosage adjustment is necessary in patients with mild hepatic insufficiency.

Jacobson TA, Armani A, McKenney JM, Guyton GR. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):47C-55C

nla safety task force report: the nonstatins

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