Mandy Leonard, PharmD, BCPS

Thomas Morledge, MD

Coenzyme Q10 supplements have been purported to be effective for treating a variety of disorders,^1,2 in particular hypertension and statin-induced myalgia.

Several studies^3–7 found that coenzyme Q10 supplementation significantly lowered blood pressure in hypertensive patients. Moreover, some trials have demonstrated that statin therapy reduces serum or muscle levels of coenzyme Q10,^8–14 prompting investigations to determine whether coenzyme Q10 deficiency is related to statin-induced muscle pain.^15–17

In this review, we discuss the efficacy and safety of coenzyme Q10 supplementation in patients with hypertension and those taking statins, and some of the caveats about using supplements that are not approved by the US Food and Drug Administration (FDA), as well as the bioavailability and quality of available formulations.

WHAT IS COENZYME Q10?

Coenzyme Q10, also known as coenzyme Q, ubidecarenone, and ubiquinone, is found in all human cells, with the highest concentrations in the heart, liver, kidney, and pancreas.^1,2 It is a potent antioxidant, a membrane stabilizer, and an integral cofactor in the mitochondrial respiratory chain, helping to generate adenosine triphosphate, the major cellular energy source.^1,2,18 It may also regulate genes associated with cell metabolism.¹⁹

RATIONALE FOR SUPPLEMENTATION

Coenzyme Q10 supplementation has been used, recommended, or studied in heart failure, hypertension, parkinsonism, mitochondrial encephalomyopathies, and other ailments.

In hypertension

Depending on the class, various antihypertensive drugs can have adverse effects such as depression, cough, and cardiac and renal dysfunction. ^20,21 Furthermore, many patients need to take more than one drug to control their blood pressure, increasing their risk of side effects. Some researchers believe coenzyme Q10 supplementation may reduce the need to take multiple antihypertensive drugs.⁵

Coenzyme Q10 appears to lower blood pressure. The exact mechanism is not known, but one theory is that it reduces peripheral resistance by preserving nitric oxide.²¹ Nitric oxide relaxes peripheral arteries, lowering blood pressure. In some forms of hypertension, superoxide radicals that inactivate nitric oxide are overproduced; coenzyme Q10, with its antioxidant effects, may prevent the inactivation of nitric oxide by these free radicals. Alternatively, coenzyme Q10 may boost the production of the prostaglandin prostacyclin (PGI₂) a potent vasodilator and inhibitor of platelet aggregation, or it may enhance the sensitivity of arterial smooth muscle to PGI₂, or both.^1,22

In patients taking statins

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), first-line agents for lowering cholesterol levels to prevent cardiovascular disease, are some of the most commonly prescribed medications.^23,24 However, statin therapy carries a risk of myopathy, which can range from muscle aches to rhabdomyolysis. ^23,24

In a clinical advisory,²⁵ the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute recommend that patients on statin therapy who experience muscle soreness, tenderness, or pain with serum creatine kinase levels 3 to 10 times the upper limit of normal should have their creatine kinase level checked weekly. If the level is 3 to 10 times the upper limit of normal, statin therapy may be continued, but if it exceeds 10 times the upper limit, then statins and other potential offending agents (eg, niacin, fibrate) need to be discontinued.

Statins inhibit the synthesis of cholesterol by reducing the production of mevalonate, a precursor of both cholesterol and coenzyme Q10. Since both cholesterol and coenzyme Q10 are produced by the same pathway, it is not surprising that statins have been reported to reduce serum and muscle coenzyme Q10 levels.^9–14 However, one study did not report a significant reduction of coenzyme Q10 levels in muscle tissue in patients treated with simvastatin 20 mg for 6 months.²⁶

Nonetheless, researchers have hypothesized that a reduction in coenzyme Q10 levels in muscle tissue causes mitochondrial dysfunction, which could increase the risk of statininduced myopathy,^13–17 and some believe that treatment with coenzyme Q10 may reduce myalgic symptoms and allow patients to remain on statin therapy.^13,24

Researchers have investigated the potential of coenzyme Q10 supplementation to reduce or prevent statin-induced myopathy.^15–17 (More on this below.)

Interestingly, a randomized, placebo-controlled trial²⁷ found that 6 months of daily therapy with simvastatin (Zocor) 20 mg or pravastatin (Pravachol) 40 mg lowered systolic and diastolic blood pressure significantly in patients with no documented history of cardiovascular disease or diabetes. A possible mechanism of statin-induced blood pressure reduction is the up-regulation of endothelial nitric oxide synthetase, a potent vasodilator. Coenzyme Q10 levels were not assessed during this study. Whether coenzyme Q10 supplementation used to treat statin-induced myalgia enhances or inhibits the antihypertensive effects of statins is not yet known.

EVIDENCE OF EFFECTIVENESS IN HYPERTENSION

A number of trials provide clinical evidence that some patients with high blood pressure may benefit from coenzyme Q10 supplementation (Table 1).^{3–7,28–31}

Rosenfeldt et al²⁸ performed a meta-analysis and found that some trials documented statistically significant reductions in diastolic or systolic blood pressure or both, while others reported negligible effects.^3,29 In one small trial,³⁰ blood pressures actually went up in patients taking coenzyme Q10. Coenzyme Q10 dosages and length of therapy varied from study to study in the meta-analysis. Only minor adverse effects such as gastrointestinal upset and headache were reported.

Yamagami et al³ randomly assigned 20 patients with hypertension and a low coenzyme Q10 level to receive 100 mg of coenzyme Q10 or placebo daily for 12 weeks. Patients continued their usual antihypertensive regimen during the study period. Blood pressures, coenzyme Q10 levels, and antihypertensive drugs used were comparable between the study groups.

After 12 weeks of therapy, the mean coenzyme Q10 level in the active-treatment group had more than doubled, from 0.704 to 1.597 μg/mL. This group also experienced a statistically significant drop in systolic blood pressure, from 167 mm Hg at baseline to 148 mm Hg at 12 weeks. In the placebo group, the systolic blood pressure was 168 mm Hg at baseline and 164 mm Hg at 12 weeks; the change was not statistically significant. Diastolic pressure was not significantly lower at 12 weeks than at baseline in either group.

The authors concluded that coenzyme Q10 supplementation brought a mild reduction in high blood pressure in patients who had low coenzyme Q10 serum levels.

Digiesi et al³¹ randomized 18 patients with essential hypertension to receive either coenzyme Q10 100 mg or placebo daily for 10 weeks. All antihypertensive therapy was discontinued at baseline. After the first 10 weeks, patients went through a 2-week washout period and then were switched to the opposite therapy for an additional 10 weeks. Mean baseline blood pressure values were 167 mm Hg systolic and 103 mm Hg diastolic.

Those taking the supplement had a statistically significant decrease in systolic and diastolic pressures (P < .001). The antihypertensive effect was noted in the 3rd or 4th week of active treatment and persisted for the duration of therapy. The effects dissipated 7 to 10 days after coenzyme Q10 was stopped.

Langsjoen et al⁵ evaluated the effects of adding coenzyme Q10 to the antihypertensive drug regimen of 109 patients who had a primary diagnosis of essential hypertension in a prospective observational study. Patients with hypertension as a secondary diagnosis and other cardiovascular diseases were excluded. Variable doses of coenzyme Q10 were given, adjusted according to clinical response and to achieve serum levels greater than 2.0 μg/mL. The average dose was 225 mg/day; the mean serum level attained was 3.02 μg/mL.

Over several months, patients taking the supplement had a reduction in mean systolic pressure from 159 mm Hg at baseline to 147 mm Hg (P < .001), and a reduction in mean diastolic pressure from 94 to 85 mm Hg (P < .001). Thirty-seven percent of patients were able to discontinue one antihypertensive drug, 11% discontinued two drugs, and 4% were able to stop taking three drugs. However, 46% remained on the same antihypertensive regimen, and 3% needed an additional drug.

Singh et al⁶ randomized 64 patients who had coronary artery disease and who had been on antihypertensive drugs for more than 1 year to receive either B-complex vitamins or coenzyme Q10 (hydrosoluble Q-Gel) 60 mg orally once daily for 8 weeks. Five patients were not available for follow-up; therefore, only 59 patients were evaluated. Fifty-five (93%) of the 59 patients were taking only one antihypertensive drug. Initial antihypertensive drug use was similar between study groups and was continued throughout the trial.

After 8 weeks of therapy, the coenzyme Q10 group had significantly lower systolic and diastolic blood pressure than the placebo group (P < .05 for both). There was also a statistically significant decrease in the dosage of antihypertensive drugs in the coenzyme Q10 group but not in the placebo group (P < .05), reflecting coenzyme Q10’s additive antihypertensive effect.

Burke et al⁷ randomized 41 men and 35 women with isolated systolic hypertension (systolic pressure 150–170 mm Hg, diastolic pressure < 90 mm Hg) to receive a twice-daily dose of 60 mg of emulsified coenzyme Q10 (hydrosoluble Q-Gel) with 150 IU of vitamin E or placebo containing vitamin E alone for 12 weeks. The study also included 5 men and 4 women with normal blood pressure, all of whom received coenzyme Q10. A total of 80 patients completed treatment. The primary goal of the study was to determine the efficacy of coenzyme Q10 in the treatment of isolated systolic hypertension in patients without comorbid conditions. Blood pressures were monitored twice a week during the trial, by the same nurse.

After 12 weeks of treatment, the mean reduction in systolic pressure in hypertensive patients on coenzyme Q10 was 17.8 ± 7.3 mm Hg. There were no significant changes in diastolic pressure in any study group with treatment. Patients with isolated systolic hypertension who were taking coenzyme Q10 had a statistically significant reduction in systolic pressure compared with baseline and placebo (P < .01 for both). Approximately 55% of patients on coenzyme Q10 achieved a reduction in systolic pressure of 4 mm Hg or greater, while 45% did not respond to therapy. The mean plasma coenzyme Q10 level of the treatment group increased from 0.47 ± 0.19 μg/mL to 2.69 ± 0.54 μg/mL after 12 weeks; however, the study did not have the statistical power to demonstrate a relationship between coenzyme Q10 levels and changes in blood pressure. Twenty-seven (34%) of the 80 patients were taking a statin while on coenzyme Q10 therapy.

STUDIES IN STATIN-INDUCED MYOPATHY

Thibault et al³² and Kim et al³³ reported that patients taking lovastatin (Mevacor) at dosages as high as 35 mg/kg/day to inhibit tumor growth achieved symptomatic relief of statin-induced musculoskeletal toxicity after coenzyme Q10 supplementation.

Caso et al¹⁵ performed a small pilot study in 32 patients to determine if coenzyme Q10 supplementation would improve myalgic symptoms in patients treated with statins. In this double-blind, randomized trial, patients received either coenzyme Q10 100 mg/day or vitamin E 400 IU/day for 30 days. The extent of muscle pain and its interference with daily activities were determined before and after therapy using the Brief Pain Inventory Questionnaire. The statins were atorvastatin (Lipitor) 10 mg or 20 mg, lovastatin 40 mg, pravastatin 40 mg, and simvastatin 10, 20, 40, and 80 mg. Five patients in the coenzyme Q10 group and four patients in the vitamin E group were taking nonsteroidal anti-inflammatory drugs before and during the trial. The intensity of muscle pain and its interference with daily activities were similar between study groups before the start of therapy.

After 30 days of treatment with coenzyme Q10, the pain intensity had decreased significantly from baseline (P < .001). In contrast, no change in pain intensity from baseline was noted in patients receiving vitamin E. The Pain Severity Score was significantly different between study groups, favoring the coenzyme Q10 group (P < .001). Sixteen of 18 patients on coenzyme Q10 reported a reduction in pain, while only 3 of 14 patients on vitamin E reported a similar response. Also, the interference of pain with daily activities significantly improved with coenzyme Q10 (P < .02), whereas vitamin E did not have a significant impact on this.

Young et al¹⁷ randomized 44 patients with prior statin-induced myalgia to receive increasing doses of simvastatin (10–40 mg/day) in combination with either coenzyme Q10 (Q-Gel) 200 mg/day or placebo. The primary goal was to determine if coenzyme Q10 supplementation would help improve statin tolerance in patients with a history of statininduced myalgia. Plasma coenzyme Q10 and lipid levels were measured at baseline and at the end of the study. The intensity of myalgia was assessed with a visual analogue scale.

At 12 weeks, the coenzyme Q10 plasma level was significantly higher in the treatment group than in the placebo group (P < .001). However, no differences were noted between groups in the number of patients who tolerated the 40-mg/day simvastatin dose (P = .34) or in the number of patients who remained on any simvastatin dose (P = .47). Additionally, myalgia scores did not differ between groups (P = .63). The authors acknowledged that there were only small increases in the myalgia pain scores reported in either group. Therefore, patients in the treatment group may not have experienced sufficiently severe muscle pain to have benefited from coenzyme Q10 supplementation.

IS COENZYME Q10 SAFE?

Studies have indicated that these supplements are well tolerated, with relatively few adverse effects or potential drug interactions.^1,2,34

The FDA does not routinely assess the purity or quality of over-the-counter coenzyme Q10 products.³⁵ However, the United States Pharmacopeia (USP) does test dietary supplements to make sure that they are not mislabeled and that they do not contain contaminants. ³⁶

A USP-verified dietary supplement should:

Contain the exact ingredients listed on the label in the listed potency and amounts
Not include harmful levels of certain contaminants such as lead, mercury, pesticides, or bacteria
Appropriately disintegrate and release its contents into the body within a specified period of time
Be produced using the FDA’s current Good Manufacturing Practices.³⁶

Side effects, contraindications, warnings

Coenzyme Q10 is a relatively safe dietary supplement. It is contraindicated in patients who are allergic to it or to any of its components.² Most clinical trials have not reported significant adverse effects that necessitated stopping therapy.³⁴ However, gastrointestinal effects such as abdominal discomfort, nausea, vomiting, diarrhea, and anorexia have occurred.^1,2,34 Allergic rash and headache have also been reported.^1,2,34 In addition, coenzyme Q10’s antiplatelet effect may increase the risk of bleeding. ^37,38 It undergoes biotransformation in the liver and is eliminated primarily via the biliary tract,³⁹ so it can accumulate in patients with hepatic impairment or biliary obstruction.

Interactions with drugs

Coenzyme Q10’s effects on platelet function may increase the risk of bleeding in patients taking antiplatelet drugs such as aspirin or clopidogrel (Plavix).^37,38 On the other hand, since it acts like vitamin K, it may counteract the anticoagulant effects of warfarin (Coumadin). ^1,2,40

Coenzyme Q10 may have an additive antihypertensive effect when given with antihypertensive drugs.⁴¹

Coenzyme Q10 may improve beta-cell function and enhance insulin sensitivity, which may reduce insulin requirements for diabetic patients.^42,43

SLOWLY ABSORBED

Coenzyme Q10 is absorbed slowly from the gastrointestinal tract, possibly because it has a high molecular weight and is not very watersoluble. ³⁹

One pharmacokinetic study found that after a single 100-mg oral dose of coenzyme Q10, the mean peak plasma levels of about 1 μg/mL occurred between 5 and 10 hours (mean 6.5 hours).⁴⁴ Coenzyme Q10 100 mg given orally three times daily produced a mean steadystate plasma level of 5.4 μg/mL; about 90% of this steady-state concentration was achieved after 4 days.³⁹

Some formulations have significantly better oral bioavailability and therefore produce higher plasma levels. Soft-gel capsules, especially those with vegetable oil or vitamin E, may have better absorption.⁴³

A pharmacokinetic study showed that the area under the curve of the plasma coenzyme Q10 concentration was more than twice as high with Q-Gel soft-gel capsules, a completely solubilized formulation, than with softgel capsules with an oil suspension, powderfilled hard-shell capsules, or regular tablets.⁴⁵ Another study reported that colloidal-Q10, a formulation contained in VESIsorb (a novel drug delivery system sold as CoQsource) had greater bioavailability than solubilized and oil-based preparations.⁴⁶ Commercially available solubilized preparations containing ubiquinol, a metabolized form of coenzyme Q10, have been shown to produce higher serum levels than solubilized products.⁴⁷

Of note: unless the manufacturer claims that its product is water-soluble, the USP does not evaluate its dissolution rate.⁴⁸ Therefore, USP-verified coenzyme Q10 products that are not water-soluble may have lower bioavailability than their solubilized counterparts.

Dry dosage forms of coenzyme Q10 (eg, tablets, capsules) may be more readily absorbed if taken with a fatty meal.⁴³

SLOWLY ELIMINATED

Taken orally, coenzyme Q10 has a low clearance rate, with an elimination half-life of about 34 hours.³⁹

After absorption, exogenous coenzyme Q10 is taken up by chylomicrons that transport it to the liver, where it is incorporated into verylow-density lipoproteins. It is then distributed to various organs, including the adrenal glands, spleen, kidneys, lungs, and heart. Coenzyme Q10 is eliminated primarily via the biliary tract. About 60% of an oral dose is eliminated in the feces during chronic oral administration.³⁹

TWICE-DAILY DOSING

A typical daily dose of coenzyme Q10 for treating hypertension is 120 to 200 mg, usually given orally in two divided doses.¹ For statininduced myopathy, 100 to 200 mg orally daily has been used.¹

Coenzyme Q10 is given in divided doses to enhance its absorption and to minimize gastrointestinal effects.^1,43 Taking it with a fatty meal may also increase its absorption.⁴³

Since solubilized forms of coenzyme Q10 and ubiquinol have significantly greater bioavailability than nonsolubilized forms, the therapeutic dose of these formulations may be lower.⁴⁷

MONITORING DURING TREATMENT

Without supplementation, the mean serum level of endogenous coenzyme Q10 has been reported to be 0.99 ± 0.30 mg/L (range 0.55– 1.87).¹⁸ Serum levels above 2 μg/mL have been associated with significant reductions in blood pressure.^5,7,28

The possible effects of coenzyme Q10 on blood pressure, blood glucose levels, serum creatine kinase levels, and myopathic symptoms should be kept in mind when monitoring patients who have hypertension,⁴¹ diabetes,^41,42 or statin-induced myalgia.^15,17 Coenzyme Q10’s possible potentiating effects on antiplatelet drugs and its inhibitory effect on warfarin should be kept in mind as well.

COST VARIES

Coenzyme Q10 is available in different dosage forms (eg, regular and rapid-release softgel capsules, regular and chewable tablets, chewable wafers, and liquid) from a variety of manufacturers. Products come in different strengths, typically ranging from 30 to 400 mg. USP-verified formulations are listed at www.usp.org/USPVerified/dietarySupplements/under “Verified Supplements.” Only USP-verified products that claim to be water-soluble meet USP dissolution requirements.

The cost varies, depending on the vendor. In general, dosage forms with greater bioavailability, such as Q-Gel and ubiquinol supplements, are more expensive. For example, a regimen of 60 mg twice daily of regular-release coenzyme Q capsules may cost approximately $20 per month, compared with $60 per month for the same supply of Q-Gel Ultra capsules. However, in some cases, supplements that produce higher serum levels may be more cost-effective.

CURRENT ROLE IN THERAPY

As an antihypertensive adjunct

Several small clinical trials have shown that coenzyme Q10 supplementation can lower blood pressure. The supplements were reported to be safe and well tolerated. Moreover, some patients with essential hypertension who were taking coenzyme Q10 were able to discontinue one or more antihypertensive drugs. A significant reduction in blood pressure with use of coenzyme Q10 would be expected to reduce the adverse consequences of hypertension in the same manner as conventional antihypertensive agents.

However, no large, double-blind, randomized study has evaluated the impact of coenzyme Q10 when taken with other antihypertensive drugs (eg, angiotensin-converting enzyme inhibitors, beta-blockers, diuretics) on specific clinical end points such as the incidence of stroke or death from a major cardiac event. Furthermore, its effects on cardiac function, exercise tolerance, and quality of life have not been determined.

The bottom line. In some cases, it seems reasonable to recommend this product as an adjunct to conventional antihypertensive therapy. Larger, well-designed clinical trials of coenzyme Q10’s antihypertensive effects on specific clinical end points such as the risk of stroke or myocardial infarction are needed to define its true therapeutic value.

As a treatment for statin-induced myalgia

Clinical evidence supporting coenzyme Q10’s use in the treatment of statin-induced myopathy is limited. Whether coenzyme Q10 is depleted from muscle tissue during statin therapy has not been confirmed. Supplementation helped reduce the severity of musculoskeletal effects of megadoses of lovastatin. However, clinical trials of coenzyme Q10 in the treatment of myalgia associated with antilipidemic statin doses did not consistently report significant improvement. Nevertheless, coenzyme Q10 has been shown to be relatively safe, with few adverse effects.

The bottom line. In some cases, coenzyme Q could be considered as a possible treatment for statin-induced myalgia, pending large-scale studies to determine if it is truly effective for this purpose.

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Marcia Wyman, PharmD
Drug Information Pharmacist, Department of Pharmacy, Cleveland Clinic

Mandy Leonard, PharmD, BCPS
Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Thomas Morledge, MD
Medical Director for Wellness Enterprise, Center for Integrative Medicine, Cleveland Clinic

Address: Marcia Wyman, PharmD, Drug Information Center, Department of Pharmacy, Hb-105, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Leonard has received honoraria from Amgen for teaching and speaking activities.

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Marcia Wyman, PharmD
Drug Information Pharmacist, Department of Pharmacy, Cleveland Clinic

Mandy Leonard, PharmD, BCPS
Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Thomas Morledge, MD
Medical Director for Wellness Enterprise, Center for Integrative Medicine, Cleveland Clinic

Address: Marcia Wyman, PharmD, Drug Information Center, Department of Pharmacy, Hb-105, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Leonard has received honoraria from Amgen for teaching and speaking activities.

Author and Disclosure Information

Marcia Wyman, PharmD
Drug Information Pharmacist, Department of Pharmacy, Cleveland Clinic

Mandy Leonard, PharmD, BCPS
Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Thomas Morledge, MD
Medical Director for Wellness Enterprise, Center for Integrative Medicine, Cleveland Clinic

Address: Marcia Wyman, PharmD, Drug Information Center, Department of Pharmacy, Hb-105, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Leonard has received honoraria from Amgen for teaching and speaking activities.

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Coenzyme Q10 supplements have been purported to be effective for treating a variety of disorders,^1,2 in particular hypertension and statin-induced myalgia.

WHAT IS COENZYME Q10?

RATIONALE FOR SUPPLEMENTATION

Coenzyme Q10 supplementation has been used, recommended, or studied in heart failure, hypertension, parkinsonism, mitochondrial encephalomyopathies, and other ailments.

In hypertension

In patients taking statins

Researchers have investigated the potential of coenzyme Q10 supplementation to reduce or prevent statin-induced myopathy.^15–17 (More on this below.)

EVIDENCE OF EFFECTIVENESS IN HYPERTENSION

A number of trials provide clinical evidence that some patients with high blood pressure may benefit from coenzyme Q10 supplementation (Table 1).^{3–7,28–31}

The authors concluded that coenzyme Q10 supplementation brought a mild reduction in high blood pressure in patients who had low coenzyme Q10 serum levels.

STUDIES IN STATIN-INDUCED MYOPATHY

IS COENZYME Q10 SAFE?

Studies have indicated that these supplements are well tolerated, with relatively few adverse effects or potential drug interactions.^1,2,34

A USP-verified dietary supplement should:

Contain the exact ingredients listed on the label in the listed potency and amounts
Not include harmful levels of certain contaminants such as lead, mercury, pesticides, or bacteria
Appropriately disintegrate and release its contents into the body within a specified period of time
Be produced using the FDA’s current Good Manufacturing Practices.³⁶

Side effects, contraindications, warnings

Interactions with drugs

Coenzyme Q10 may have an additive antihypertensive effect when given with antihypertensive drugs.⁴¹

Coenzyme Q10 may improve beta-cell function and enhance insulin sensitivity, which may reduce insulin requirements for diabetic patients.^42,43

SLOWLY ABSORBED

Coenzyme Q10 is absorbed slowly from the gastrointestinal tract, possibly because it has a high molecular weight and is not very watersoluble. ³⁹

Dry dosage forms of coenzyme Q10 (eg, tablets, capsules) may be more readily absorbed if taken with a fatty meal.⁴³

SLOWLY ELIMINATED

Taken orally, coenzyme Q10 has a low clearance rate, with an elimination half-life of about 34 hours.³⁹

TWICE-DAILY DOSING

A typical daily dose of coenzyme Q10 for treating hypertension is 120 to 200 mg, usually given orally in two divided doses.¹ For statininduced myopathy, 100 to 200 mg orally daily has been used.¹

Coenzyme Q10 is given in divided doses to enhance its absorption and to minimize gastrointestinal effects.^1,43 Taking it with a fatty meal may also increase its absorption.⁴³

Since solubilized forms of coenzyme Q10 and ubiquinol have significantly greater bioavailability than nonsolubilized forms, the therapeutic dose of these formulations may be lower.⁴⁷

MONITORING DURING TREATMENT

COST VARIES

CURRENT ROLE IN THERAPY

As an antihypertensive adjunct

As a treatment for statin-induced myalgia

Coenzyme Q10 supplements have been purported to be effective for treating a variety of disorders,^1,2 in particular hypertension and statin-induced myalgia.

WHAT IS COENZYME Q10?

RATIONALE FOR SUPPLEMENTATION

Coenzyme Q10 supplementation has been used, recommended, or studied in heart failure, hypertension, parkinsonism, mitochondrial encephalomyopathies, and other ailments.

In hypertension

In patients taking statins

Researchers have investigated the potential of coenzyme Q10 supplementation to reduce or prevent statin-induced myopathy.^15–17 (More on this below.)

EVIDENCE OF EFFECTIVENESS IN HYPERTENSION

A number of trials provide clinical evidence that some patients with high blood pressure may benefit from coenzyme Q10 supplementation (Table 1).^{3–7,28–31}

The authors concluded that coenzyme Q10 supplementation brought a mild reduction in high blood pressure in patients who had low coenzyme Q10 serum levels.

STUDIES IN STATIN-INDUCED MYOPATHY

IS COENZYME Q10 SAFE?

Studies have indicated that these supplements are well tolerated, with relatively few adverse effects or potential drug interactions.^1,2,34

A USP-verified dietary supplement should:

Contain the exact ingredients listed on the label in the listed potency and amounts
Not include harmful levels of certain contaminants such as lead, mercury, pesticides, or bacteria
Appropriately disintegrate and release its contents into the body within a specified period of time
Be produced using the FDA’s current Good Manufacturing Practices.³⁶

Side effects, contraindications, warnings

Interactions with drugs

Coenzyme Q10 may have an additive antihypertensive effect when given with antihypertensive drugs.⁴¹

Coenzyme Q10 may improve beta-cell function and enhance insulin sensitivity, which may reduce insulin requirements for diabetic patients.^42,43

SLOWLY ABSORBED

Coenzyme Q10 is absorbed slowly from the gastrointestinal tract, possibly because it has a high molecular weight and is not very watersoluble. ³⁹

Dry dosage forms of coenzyme Q10 (eg, tablets, capsules) may be more readily absorbed if taken with a fatty meal.⁴³

SLOWLY ELIMINATED

Taken orally, coenzyme Q10 has a low clearance rate, with an elimination half-life of about 34 hours.³⁹

TWICE-DAILY DOSING

A typical daily dose of coenzyme Q10 for treating hypertension is 120 to 200 mg, usually given orally in two divided doses.¹ For statininduced myopathy, 100 to 200 mg orally daily has been used.¹

Coenzyme Q10 is given in divided doses to enhance its absorption and to minimize gastrointestinal effects.^1,43 Taking it with a fatty meal may also increase its absorption.⁴³

Since solubilized forms of coenzyme Q10 and ubiquinol have significantly greater bioavailability than nonsolubilized forms, the therapeutic dose of these formulations may be lower.⁴⁷

MONITORING DURING TREATMENT

COST VARIES

CURRENT ROLE IN THERAPY

As an antihypertensive adjunct

As a treatment for statin-induced myalgia

References

Jelin JM, Gregory PJ, et al. Natural medicines comprehensive database/compiled by the editors of Pharmacist’s Letter, Prescriber’s Letter. 11th ed. Stockton, CA: Therapeutic Research Faculty; 2009:452–457.
Fetrow CW, Avila JR. Professional’s Handbook of Complementary & Alternative Medicines. 2nd ed. Springhouse, PA: Springhouse; 2001:211–215.
Yamagami T, Takagi M, Akagami H, et al. Effect of coenzyme Q10 on essential hypertension, a double-blind controlled study. In:Folkers K, Yamamura Y, editors. Biomedical and Clinical Aspects of Coenzyme Q10: Proceedings of the Fifth International Symposium on the Biomedical and Clinical Aspects of Coenzyme Q10, vol 5. Amsterdam: Elsevier Science Publishers; 1986:337–343.
Digiesi V, Cantini F, Oradei A, et al. Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994; 15(suppl):S257–S263.
Langsjoen P, Langsjoen P, Willis R, Folkers K. Treatment of essential hypertension with coenzyme Q10. Mol Aspects Med 1994; 15(suppl):S265–S272.
Singh RB, Niaz MA, Rastogi SS, Shukla PK, Thakur AS. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens 1999; 13:203–208.
Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J 2001; 94:1112–1117.
De Pinieux G, Chariot P, Ammi-Saïd M, et al. Lipidlowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42:333–337.
Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997; 18(suppl):S137–S144.
Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33:226–229.
Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q10 levels in humans. Proc Natl Acad Sci U S A 1990; 87:8931–8934.
Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q10 (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993; 46:1055–1057.
Lamperti C, Naini AB, Lucchini V, et al. Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol 2005; 62:1709–1712.
Päivä H, Thelen KM, Van Coster R, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 2005; 78:60–68.
Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007; 99:1409–1412.
Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49:2231–2237.
Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol 2007; 100:1400–1403.
Berthold HK, Naini A, Di Mauro S, et al. Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf 2006; 29:703–712.
Groneberg DA, Kindermann B, Althammer M, et al. Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells. Int J Biochem Cell Biol 2005; 37:1208–1218.
Hadj A, Pepe S, Rosenfeldt F. The clinical application of metabolic therapy for cardiovascular disease. Heart Lung Circ 2007; 16(suppl 3):S56–S64.
Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion 2007; 7(suppl 1):S154–S167.
Lönnrot K, Pörsti I, Alho H, Wu X, Hervonen A, Tolvanen JP. Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats. Br J Pharmacol 1998; 124:1500–1506.
Sewright KA, Clarkson PM, Thompson PD. Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep 2007; 9:389–396.
Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008; 8:66–72.
Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002; 106:1024–1028.
Laaksonen R, Jokelainen K, Laakso J, et al. The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 1996; 77:851–854.
Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH. Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial. Arch Intern Med 2008; 168:721–727.
Rosenfeldt FL, Haas SJ, Krum H, et al. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens 2007; 21:297–306.
Yamagami T, Shibata N, Folkers K. Bioenergetics in clinical medicine. Studies on coenzyme Q10 and essential hypertension. Res Commun Chem Pathol Pharmacol 1975; 11:273–288.
Yamagami T, Shibata N, Folkers K. Study of coenzyme Q10. In:Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q10: proceedings of the International Symposium on Coenzyme Q10, held at Lake Yamanaka, Japan, September 16/17, 1976, a Naito Foundation symposium. Amsterdam: Elsevier Scientific Publishing Company; 1977:231–242.
Digiesi V, Cantini F, Brodbeck B. Effect of coenzyme Q10 on essential arterial hypertension. Curr Ther Res; 1990; 47:841–845.
Thibault A, Samid D, Tompkins AC, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 1996; 2:483–491.
Kim WS, Kim MM, Choi HJ, et al. Phase II study of high-dose lova-statin in patients with advanced gastric adenocarcinoma. Invest New Drugs 2001; 19:81–83.
Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors 2008; 32:199–208.
US Food and Drug Administration. Consumer Information on Dietary Supplements. Overview of Dietary Supplements. http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/. Accessed May 25, 2010.
US Pharmacopeia. The USP Dietary Supplement Verification Program http://www.usp.org/USPVerified/dietary-Supplements/. Accessed May 25, 2010.
Serebruany VL, Ordonez JV, Herzog WR, et al. Dietary coenzyme Q10 supplementation alters platelet size and inhibits human vitronectin (CD51/CD61) receptor expression. J Cardiovasc Pharmacol 1997; 29:16–22.
A close look at coenzyme Q10 and policosanol. Do these supplements live up to their claims for improving heart health? Harv Heart Lett 2002; 13:6.
Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990; 30:596–608.
Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutr Rev 2007; 65:286–293.
Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician 2005; 72:1065–1070.
Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 2002; 56:1137–1142.
Pepping J. Coenzyme Q10. Am J Health Syst Pharm 1999; 56:519–521.
Tomono Y, Hasegawa J, Seki T, Motegi K, Morishita N. Pharmacokinetic study of deuterium-labelled coenzyme Q10 in man. Int J Clin Pharmacol Ther Toxicol 1986; 24:536–541.
Chopra RK, Goldman R, Sinatra ST, Bhagavan HN. Relative bioavailability of coenzyme Q10 formulations in human subjects. Int J Vitam Nutr Res 1998; 68:109–113.
Liu ZX, Artmann C. Relative bioavailability comparison of different coenzyme Q10 formulations with a novel delivery system. Altern Ther Health Med 2009; 15:42–46.
Bhagavan HN, Chopra RK. Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 2007; 7(suppl 1):S78–S88.
The United States Pharmacopeia. Ubidecarenone Capsules Monograph. 32nd Revision. Baltimore: United Book Press, 2009:1080.

References

Jelin JM, Gregory PJ, et al. Natural medicines comprehensive database/compiled by the editors of Pharmacist’s Letter, Prescriber’s Letter. 11th ed. Stockton, CA: Therapeutic Research Faculty; 2009:452–457.
Fetrow CW, Avila JR. Professional’s Handbook of Complementary & Alternative Medicines. 2nd ed. Springhouse, PA: Springhouse; 2001:211–215.
Yamagami T, Takagi M, Akagami H, et al. Effect of coenzyme Q10 on essential hypertension, a double-blind controlled study. In:Folkers K, Yamamura Y, editors. Biomedical and Clinical Aspects of Coenzyme Q10: Proceedings of the Fifth International Symposium on the Biomedical and Clinical Aspects of Coenzyme Q10, vol 5. Amsterdam: Elsevier Science Publishers; 1986:337–343.
Digiesi V, Cantini F, Oradei A, et al. Coenzyme Q10 in essential hypertension. Mol Aspects Med 1994; 15(suppl):S257–S263.
Langsjoen P, Langsjoen P, Willis R, Folkers K. Treatment of essential hypertension with coenzyme Q10. Mol Aspects Med 1994; 15(suppl):S265–S272.
Singh RB, Niaz MA, Rastogi SS, Shukla PK, Thakur AS. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens 1999; 13:203–208.
Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J 2001; 94:1112–1117.
De Pinieux G, Chariot P, Ammi-Saïd M, et al. Lipidlowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42:333–337.
Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997; 18(suppl):S137–S144.
Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33:226–229.
Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q10 levels in humans. Proc Natl Acad Sci U S A 1990; 87:8931–8934.
Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q10 (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993; 46:1055–1057.
Lamperti C, Naini AB, Lucchini V, et al. Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol 2005; 62:1709–1712.
Päivä H, Thelen KM, Van Coster R, et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 2005; 78:60–68.
Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins. Am J Cardiol 2007; 99:1409–1412.
Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol 2007; 49:2231–2237.
Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol 2007; 100:1400–1403.
Berthold HK, Naini A, Di Mauro S, et al. Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial. Drug Saf 2006; 29:703–712.
Groneberg DA, Kindermann B, Althammer M, et al. Coenzyme Q10 affects expression of genes involved in cell signalling, metabolism and transport in human CaCo-2 cells. Int J Biochem Cell Biol 2005; 37:1208–1218.
Hadj A, Pepe S, Rosenfeldt F. The clinical application of metabolic therapy for cardiovascular disease. Heart Lung Circ 2007; 16(suppl 3):S56–S64.
Pepe S, Marasco SF, Haas SJ, Sheeran FL, Krum H, Rosenfeldt FL. Coenzyme Q10 in cardiovascular disease. Mitochondrion 2007; 7(suppl 1):S154–S167.
Lönnrot K, Pörsti I, Alho H, Wu X, Hervonen A, Tolvanen JP. Control of arterial tone after long-term coenzyme Q10 supplementation in senescent rats. Br J Pharmacol 1998; 124:1500–1506.
Sewright KA, Clarkson PM, Thompson PD. Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep 2007; 9:389–396.
Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol Neurosci Rep 2008; 8:66–72.
Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002; 106:1024–1028.
Laaksonen R, Jokelainen K, Laakso J, et al. The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 1996; 77:851–854.
Golomb BA, Dimsdale JE, White HL, Ritchie JB, Criqui MH. Reduction in blood pressure with statins: results from the UCSD Statin Study, a randomized trial. Arch Intern Med 2008; 168:721–727.
Rosenfeldt FL, Haas SJ, Krum H, et al. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. J Hum Hypertens 2007; 21:297–306.
Yamagami T, Shibata N, Folkers K. Bioenergetics in clinical medicine. Studies on coenzyme Q10 and essential hypertension. Res Commun Chem Pathol Pharmacol 1975; 11:273–288.
Yamagami T, Shibata N, Folkers K. Study of coenzyme Q10. In:Folkers K, Yamamura Y, editors. Biomedical and clinical aspects of coenzyme Q10: proceedings of the International Symposium on Coenzyme Q10, held at Lake Yamanaka, Japan, September 16/17, 1976, a Naito Foundation symposium. Amsterdam: Elsevier Scientific Publishing Company; 1977:231–242.
Digiesi V, Cantini F, Brodbeck B. Effect of coenzyme Q10 on essential arterial hypertension. Curr Ther Res; 1990; 47:841–845.
Thibault A, Samid D, Tompkins AC, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 1996; 2:483–491.
Kim WS, Kim MM, Choi HJ, et al. Phase II study of high-dose lova-statin in patients with advanced gastric adenocarcinoma. Invest New Drugs 2001; 19:81–83.
Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors 2008; 32:199–208.
US Food and Drug Administration. Consumer Information on Dietary Supplements. Overview of Dietary Supplements. http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/. Accessed May 25, 2010.
US Pharmacopeia. The USP Dietary Supplement Verification Program http://www.usp.org/USPVerified/dietary-Supplements/. Accessed May 25, 2010.
Serebruany VL, Ordonez JV, Herzog WR, et al. Dietary coenzyme Q10 supplementation alters platelet size and inhibits human vitronectin (CD51/CD61) receptor expression. J Cardiovasc Pharmacol 1997; 29:16–22.
A close look at coenzyme Q10 and policosanol. Do these supplements live up to their claims for improving heart health? Harv Heart Lett 2002; 13:6.
Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular disease. J Clin Pharmacol 1990; 30:596–608.
Singh U, Devaraj S, Jialal I. Coenzyme Q10 supplementation and heart failure. Nutr Rev 2007; 65:286–293.
Bonakdar RA, Guarneri E. Coenzyme Q10. Am Fam Physician 2005; 72:1065–1070.
Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 2002; 56:1137–1142.
Pepping J. Coenzyme Q10. Am J Health Syst Pharm 1999; 56:519–521.
Tomono Y, Hasegawa J, Seki T, Motegi K, Morishita N. Pharmacokinetic study of deuterium-labelled coenzyme Q10 in man. Int J Clin Pharmacol Ther Toxicol 1986; 24:536–541.
Chopra RK, Goldman R, Sinatra ST, Bhagavan HN. Relative bioavailability of coenzyme Q10 formulations in human subjects. Int J Vitam Nutr Res 1998; 68:109–113.
Liu ZX, Artmann C. Relative bioavailability comparison of different coenzyme Q10 formulations with a novel delivery system. Altern Ther Health Med 2009; 15:42–46.
Bhagavan HN, Chopra RK. Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 2007; 7(suppl 1):S78–S88.
The United States Pharmacopeia. Ubidecarenone Capsules Monograph. 32nd Revision. Baltimore: United Book Press, 2009:1080.

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Cleveland Clinic Journal of Medicine - 77(7)

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Cleveland Clinic Journal of Medicine - 77(7)

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Coenzyme Q10: A therapy for hypertension and statin-induced myalgia?

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Coenzyme Q10: A therapy for hypertension and statin-induced myalgia?

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KEY POINTS

In some clinical trials, coenzyme Q10 supplements significantly lowered diastolic and systolic blood pressure.
Statins may lower coenzyme Q10 serum levels, and some investigators have evaluated the relationship between coenzyme Q10 deficiency and statin-related myalgia, but more evidence is needed to support the use of coenzyme Q10 supplements to prevent or treat myalgia.
Coenzyme Q10 supplementation appears to be relatively safe. Most clinical trials have not reported significant side effects that necessitated stopping therapy. Gastrointestinal effects include abdominal discomfort, nausea, vomiting, diarrhea, and anorexia. Allergic rash and headache have also been reported.

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Rebecca Corey, PharmD, BCPS

Acetaminophen: Old drug, new warnings

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Acetaminophen: Old drug, new warnings

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Amy Schilling, PharmD

Bijan Eghtesad, MD

Editor’s note: Portions of this article are based on an article previously published in an internal Cleveland Clinic publication, Pharmacotherapy Update. The version here has been revised, updated, and peer-reviewed.

Acetaminophen (Tylenol, also known as paracetamol, N-acetyl-p-aminophenol, and APAP) is a popular antipyretic and analgesic found in many over-the-counter and prescription products, including cough-and-cold remedies and narcotic pain relievers (Table 1).¹

This drug is generally considered safe, but high doses can be toxic. The number of overdoses is worrisome. In 2006 alone, the American Association of Poison Control Centers implicated acetaminophen in nearly 140,000 poisoning cases, in which more than 100 patients died.² It is responsible for more emergency room visits than any other drug on the market.

According to a position statement from the American Association for the Study of Liver Diseases (AASLD),³ the incidence of acetaminophen-related liver toxicity has been steadily increasing over the past decade, and this drug is now the most common cause of acute liver failure.

MANY OVERDOSES ARE UNINTENTIONAL

Cases of acetaminophen-related liver toxicity can be categorized as either intentional (ie, due to a suicide attempt) or unintentional (ie, due to multiple therapeutic but excessive doses over a period of time, usually more than 3 days).

Up to 50% of cases are unintentional. Bower et al⁴ reviewed cases of acute liver failure that occurred in the Atlanta, GA, area between November 2000 and October 2004. Acetaminophen was the most common cause in adult patients. Of greater concern is that 61% of the acetaminophen-related cases were due to unintentional overdose. According to the Institute for Safe Medication Practices,⁵ one hospital (not named) reported that an average of one patient per day was given more than the recommended maximum daily acetaminophen dose of 4 g while in the hospital.

Many patients take more than one acetaminophen product

Unintentional overdoses or “therapeutic misadventures” are most often due to taking multiple products that contain acetaminophen, taking acetaminophen-narcotic combinations, and impulsive behavior involving a lack of understanding of possible injury in consuming multiple acetaminophen-containing products.³

In the US Food and Drug Administration (FDA) Medwatch Database, in 307 cases of unintentional acetaminophen overdose between 1998 and 2001, 25% of patients had been taking more than one acetaminophencontaining product.⁵

Larson et al⁶ found that one-third of patients who had had an unintentional acetaminophen overdose were taking an acetaminophen-narcotic combination in addition to another acetaminophen-containing product.

Many consumers don’t know they are taking acetaminophen

Many consumers don’t know that some of the drugs they take contain acetaminophen. This may be because many drug labels contain abbreviations for acetaminophen such as “APAP” or have inconsistent formatting that makes it difficult to determine if the product contains acetaminophen.

Others may not be aware of the total maximum recommended daily dose or may not be able to calculate the total daily intake from the information on the label. The problem is not only with over-the-counter products. For example, if a physician prescribes one or two tablets of hydrocodone/acetaminophen (Vicodin) 5 mg/500 mg every 4 to 6 hours, a patient could easily exceed the recommended maximum daily dose of 4 g of acetaminophen.

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

Chronic alcohol use (ie, more than three drinks per day)
Malnutrition
Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

Acetaminophen is an effective antipyretic and analgesic, but its anti-inflammatory properties are minimal, especially compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, acetaminophen is preferred over NSAIDs in some patients because it carries a lower risk of gastrointestinal toxicity (eg, ulceration, bleeding) and so may be better tolerated.¹

INDICATIONS AND DOSAGE

Acetaminophen is indicated for mild to moderate pain or fever, including the pain of osteoarthritis. It is not recommended for chronic inflammatory conditions such as rheumatoid arthritis, since it lacks anti-inflammatory properties.

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

The current package label recommends that the total daily dose not exceed 4 g in most adults. Lower maximum daily doses (eg, 2 g) are recommended in patients who may be at higher risk of hepatotoxicity, such as those who drink heavily, are malnourished, or take enzyme-inducing drugs. Tylenol products currently include an alcohol warning, advising those who consume three or more alcoholic drinks a day to ask their doctor if they should take acetaminophen.

In children up to 12 years of age, the recommended dosage is 10 to 15 mg/kg orally or rectally every 4 to 6 hours. The maximum dosing for children in this age group should not exceed five doses (or 50 to 75 mg/kg) in 24 hours.⁷ In children under age 2 or weighing less than 11 kg, acetaminophen should only be used under the direction of a physician.

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Most of the acetaminophen in the blood undergoes conjugation in the liver with glucuronic acid (40%–67%) and sulfates (20%–46%).⁹ The conjugated metabolites, as well as small amounts that have been hydroxylated and deacetylated, are excreted in the urine (Figure 1).

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²

MANAGING ACETAMINOPHENHEN OVERDOSE

Measuring serum acetaminophen levels may be useful in cases of single, acute overdoses if the time since ingestion is known. The Rumack-Matthew nomogram (Figure 2), used in cases of acute acetaminophen overdose, predicts the probability of hepatotoxicity on the basis of plasma levels and time after ingestion.^13–15

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Acetylcysteine is the antidote for acetaminophen toxicity and should be given within 8 hours of ingestion for maximal protection against hepatic injury in patients whose serum acetaminophen levels are above the “possible” toxicity line on the nomogram.¹⁵ If acetaminophen overdose is suspected but the time elapsed since ingestion cannot be determined, acetylcysteine should be given immediately regardless of the quantity of acetaminophen ingested. ¹⁶ In cases of unintentional overdose, it is often given at the discretion of the physician.

Acetylcysteine limits the toxicity of acetaminophen by increasing glutathione stores, binding with NAPQI as a substitute for glutathione, and enhancing sulfate conjugation.⁶ It may further limit acetaminophen toxicity by nonspecific mechanisms including anti-inflammatory, antioxidant, inotropic, and vasodilating effects.⁶ In addition, it may prevent further hepatic damage in any patient thought to have acetaminophen-related liver toxicity even beyond the first 12 hours of an overdose.¹

Acetylcysteine is available in an oral (Mucomyst) and an intravenous (Acetadote) formulation, which are similar in efficacy. Because many patients find the taste of the oral solution unpleasant and difficult to tolerate, it should be diluted in a 1:3 ratio with cola, orange juice, or other drink to mask its flavor. This mixture should be used within 1 hour of preparation.

Anaphylactoid reactions have occurred in patients receiving intravenous acetylcysteine for acetaminophen overdose soon after the infusion was started, most commonly during the loading dose. The frequency of infusion-related reactions has been reported to be 0.2% to 20.8%.¹⁵

The recommended dosage for intravenous acetylcysteine is a loading dose of 150 mg/kg given over 60 minutes, followed by a second dose of 50 mg/kg given over 4 hours, and finally a third dose of 100 mg/kg given over 16 hours.¹⁵ For oral acetylcysteine, the loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 additional doses.¹⁷

Other measures

Activated charcoal can be used if the patient presents within 1 to 2 hours after taking acetaminophen. However, the rapid gastrointestinal absorption of acetaminophen makes this treatment ineffective in most cases.⁹

Liver transplantation. In patients with acute liver failure and a poor prognosis, early referral to a liver transplant center is essential. The King’s College criteria (Table 2),¹⁸ a widely used prognostic model in patients with acute liver failure, are used to predict the need for liver transplantation. They are based on the arterial pH, the PT and INR, the severity of encephalopathy, and the serum creatinine concentration.

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Ostapowicz et al,¹⁹ as part of the Acute Liver Failure Study Group, in 2002 prospectively characterized the short-term outcomes of acute liver failure in a large number of patients at 17 tertiary care centers in the United States over approximately 41 months. All centers except one performed liver transplants. Eligible patients had to meet criteria for acute liver failure, including an INR higher than 1.5, evidence of hepatic encephalopathy, and presentation within 26 weeks of illness onset without apparent chronic liver disease.

Of the 308 cases of acute liver failure, 120 (39%) were from acetaminophen overdose, making this drug the most common cause of acute liver failure. Forty-four (37%) of the patients with acetaminophen-related acute liver failure were trying to commit suicide, 57% of cases were accidental, and the remaining reasons for acetaminophen overdose were unknown. The median amount ingested was 13.2 g/day (range 2.6–75 g), and 99 (83%) of the 120 patients took more than 4 g/day.

The patients with acetaminophen-related acute liver toxicity differed from those with other causes of acute liver failure such as idiosyncratic drug reactions or indeterminate causes. The acetaminophen group had a shorter duration of disease and higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine than those with acute liver failure from other causes. They also had lower bilirubin levels and a lower arterial pH.

Rates of liver transplantation were 6% in the acetaminophen group, 53% in the group with other drug-induced liver toxicity, 51% in the indeterminate group, and 36% in the remaining groups. Of the acetaminophen group, 47% met the criteria for transplantation, but only 57% of those eligible were listed for transplantation. Those excluded from the transplant list had medical contraindications or were excluded for psychosocial reasons. The short-term transplant-free survival rate was 68% in the acetaminophen group.

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Larson et al,²⁰ as part of the Acute Liver Failure Study Group, examined the incidence, risk factors, and outcomes of acetaminopheninduced acute liver failure at 22 tertiary care centers in the United States over a 6-year period. Of the 662 patients in the study, 302 had acetaminophen-related toxicity and 275 were included in the final analysis; some of them had been included in the study by Ostapowicz et al.¹⁹ During the study period, the number of cases of acute liver toxicity related to acetaminophen increased from 28% to 51%.

Of the patients enrolled in the study, 56% met the criteria for potentially toxic acetaminophen ingestion. Of those who met the criteria, 77% had detectable acetaminophen levels in their serum, and 91% had ALT levels higher than 1,000 IU/L. The time between ingestion and symptom onset ranged from 1 to 32 days, and the median dose was 24 g (range 1.2–180 g).

Of the overdose cases, 48% were unintentional, 44% were intentional, and the remaining 8% had no definable reason. Of the patients in the unintentional-overdose group, 38% were using more than one acetaminophen-containing product and 63% were taking combination products containing narcotics. Overeall, 44% of patients reported using narcotic-acetaminophen combination products. The unintentional-overdose group had lower serum acetaminophen levels than the intentional-overdose group, but they were more likely to present with severe hepatic encephalopathy.

The number of patients with an unintentional overdose was worrisome. Furthermore, one-third of the patients who were receiving an acetaminophen-narcotic combination product were taking an additional acetaminophencontaining product. The authors concluded that unintentional overdose is the leading cause of acetaminophen-related hepatotoxicity, and efforts to limit the over-the-counter package size and to restrict prescriptions of acetaminophen-narcotic combinations may be necessary to decrease the incidence of this preventable cause of acute liver failure.

Findings in children

Squires et al²¹ and the Pediatric Acute Liver Failure Study Group examined the pathogenesis, treatment, and outcome of acute liver failure in children (any age from birth to 18 years) with no previous evidence of chronic liver disease, evidence of acute liver injury, or hepatic-based coagulopathy. From December 1999 to December 2004, 348 patients were enrolled.

Fourteen percent of the cases were due to acetaminophen. The median dose of acetaminophen ingested was 183 mg/kg. Most of these patients were white and female, and 96% were over age 3. Hepatic encephalopathy was more common in the non-acetaminophen groups than in the acetaminophen group, although this is often difficult to assess in infants and children. Children with acetaminophen toxicity had the highest rate of spontaneous recovery: 45 (94%) of 48 recovered.

Although there are fewer acetaminophenrelated cases of acute liver failure in children than in adults, the use of acetaminophen in children is still worrisome. The authors concluded that if they do not have hepatic encephalopathy, children with acetaminopheninduced liver toxicity have an excellent prognosis.

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
Some patients may be more prone to liver injury from acetaminophen.
The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
Consumers are unaware of the risk of liver toxicity with acetaminophen.
Prescription products are not always clearly labeled with acetaminophen as an ingredient.
Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

In addition, an FDA advisory panel recommended decreasing the maximum recommended daily dose (possibly to 3,250 mg/day in adults, although this is not final) to help prevent overdoses, and reducing the maximum amount in a single nonprescription dose of the drug to 650 mg.²³ The panel also voted (by a narrow margin) to ban all acetaminophen-narcotic combination products.

As of this writing, the FDA has not adopted these recommendations. (Although the FDA is not obliged to follow the advice of its advisory panels, in most cases it does.) The recommendations about acetaminophen could take years to implement fully.

THE UNITED KINGDOM ACTED IN 1998

In response to a rising number of analgesicrelated deaths, the United Kingdom enacted legislation in 1998 to limit the package size available to consumers.²⁴ Packages sold in general stores can contain no more than 16 capsules, while those sold in pharmacies can contain 24. Blister packs were also introduced to make it harder for people to impulsively take handfuls of tablets.²⁵

Two studies since then both found that the number of deaths related to paracetamol (as acetaminophen is known in the United Kingdom) had fallen since the legislation was implemented.^24,26 Greene et al²⁷ found that patients who ingested potentially toxic doses of paracetamol had obtained the drug “in a manner contravening the 1998 legislation.”²⁷ In other words, shops in London were not obeying the law.

SUMMARY

The new labeling and the proposed changes are sensible and draw needed attention to the problem of acetaminophen toxicity. To prevent unintentional acetaminophen overdoses, education of patients and health care professionals is urgently needed so that the dangers of consuming excess acetaminophen daily are understood.

References

Burke A, Smyth EM, Fitzgerald GA. Analgesic-antipyretic agents: pharmacotherapy of gout. In:Brunton LL, Lazo JS, Parker K, editors. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill, 2006:671–716.
Bronstein AC, Spyker DA, Cantilena LR, Green J, Rumack BH, Heard SE. 2006 Annual Report of the American Association of Poison Control Centers National Poison Data System (NPDS). Clin Toxicol (Phila) 2007; 45:815–917.
Schwartz J, Stravitz T, Lee WM; American Association for the Study of Liver Disease Study Group. AASLD position on acetaminophen. www.aasld.org/about/publicpolicy/Documents/Public%2520Policy%2520Documents/AcetaminophenPosition.pdf.
Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Populationbased surveillance for acute liver failure. Am J Gastroenterol 2007; 102:2459–2463.
Institute for Safe Medication Practices. How are you preventing acetaminophen overdoses? www.ismp.org/newsletters/acutecare/articles/20030808.asp. Accessed 11/17/2009.
Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11:525–548.
Tylenol package insert. Fort Washington, PA: McNeil-PPC Inc.; 1999.
Bizovi KE, Hendrickson RG. Chapter 34. Acetaminophen. In:Hoffman RS, Nelson LS, Howland MA, Lewin NA, Flomenbaum NE, Goldfrank LR, editors. Goldfrank’s Manual of Toxicologic Emergencies. 3rd ed. McGraw-Hill: New York, 2007. www.accessemergencymedicine.com/content.aspx?aID=88781. Accessed 11/7/2009.
Hung OL, Nelson LS. Chapter 171. Acetaminophen. In:Tintinalli JE, Kelen GD, Stapcynski S, editors. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 6th ed. McGraw-Hill: New York, 2004. www.accessmedicine.com/content.aspx?aID=602606. Accessed 11/17/2009.
Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296:87–93.
American Academy of Pediatrics Committee on Drugs. Acetaminophen toxicity in children. Pediatrics 2001; 108:1020–1024.
Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am 2008; 92:761–794.
Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359:285–292.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871–876.
Acetadote package insert. Nashville, TN: Cumberland Pharmaceuticals; 2008Dec.
Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41:1179–1197.
Product Information: acetylcysteine inhalation solution, acetylcysteine inhalation solution. Hospira,Inc, Lake Forest, IL, 2004.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.
Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954.
Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372.
Squires RH, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the Pediatric Acute Liver Failure Study Group. J Pediatr 2006; 148:652–658.
US Food and Drug Administration. Questions and answers on final rule for labeling changes to over-the-counter pain relievers. www.fda.gov/Drugs/NewsEvents/ucm144068.htm. Accessed 10/30/2009.
Perrone M. FDA panel recommends smaller doses of painkillers. Associated Press. Adelphi, MD. June 30, 2009.
Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ 2004; 329:1076.
Hughes B, Durran A, Langford NJ, Mutimer D. Paracetamol poisoning—impact of pack size restrictions. J Clin Pharmacol Ther 2003; 28:307–310.
Wilkinson S, Taylor G, Templeton L, Mistral W, Salter E, Bennett P. Admissions to hospital for deliberate self-harm in England 1995–2000: an analysis of hospital episode statistics. J Public Health Med 2002; 24:179–183.
Greene SL, Dargan PI, Leman P, Jones AL. Paracetamol availability and recent changes in paracetamol poisoning: is the 1998 legislation limiting availability of paracetamol being followed? Postgrad Med J 2006; 82:520–523.

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Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Bijan Eghtesad, MD
Hepato-pancreato-biliary and Transplant Surgery, Digestive Disease Institute, Cleveland Clinic

Address: Amy Schilling, PharmD, Department of Pharmacy, JJN1-02, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Rebecca Corey, PharmD, BCPS
Liver Transplantation Clinical Pharmacy Specialist, Department of Pharmacy, Cleveland Clinic

Mandy Leonard, PharmD, BCPS
Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Bijan Eghtesad, MD
Hepato-pancreato-biliary and Transplant Surgery, Digestive Disease Institute, Cleveland Clinic

Address: Amy Schilling, PharmD, Department of Pharmacy, JJN1-02, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Department of Pharmacy, Cleveland Clinic

Rebecca Corey, PharmD, BCPS
Liver Transplantation Clinical Pharmacy Specialist, Department of Pharmacy, Cleveland Clinic

Mandy Leonard, PharmD, BCPS
Assistant Director, Drug Information Services and Formulary Management, Department of Pharmacy, Cleveland Clinic

Bijan Eghtesad, MD
Hepato-pancreato-biliary and Transplant Surgery, Digestive Disease Institute, Cleveland Clinic

Address: Amy Schilling, PharmD, Department of Pharmacy, JJN1-02, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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MANY OVERDOSES ARE UNINTENTIONAL

Many patients take more than one acetaminophen product

Many consumers don’t know they are taking acetaminophen

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

Chronic alcohol use (ie, more than three drinks per day)
Malnutrition
Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

INDICATIONS AND DOSAGE

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

NAPQI is a toxic metabolite

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

HOW ACETAMINOPHEN CAN INJURE THE LIVER

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

In acute intentional overdose, signs may not be apparent immediately

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

MANAGING ACETAMINOPHENHEN OVERDOSE

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Other measures

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Findings in children

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
Some patients may be more prone to liver injury from acetaminophen.
The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
Consumers are unaware of the risk of liver toxicity with acetaminophen.
Prescription products are not always clearly labeled with acetaminophen as an ingredient.
Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

THE UNITED KINGDOM ACTED IN 1998

SUMMARY

MANY OVERDOSES ARE UNINTENTIONAL

Many patients take more than one acetaminophen product

Many consumers don’t know they are taking acetaminophen

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

Chronic alcohol use (ie, more than three drinks per day)
Malnutrition
Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

INDICATIONS AND DOSAGE

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

NAPQI is a toxic metabolite

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

HOW ACETAMINOPHEN CAN INJURE THE LIVER

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

In acute intentional overdose, signs may not be apparent immediately

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

MANAGING ACETAMINOPHENHEN OVERDOSE

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Other measures

FINDINGS FROM LARGE REGISTRIES

Findings in adults

Overall, 11% of the patients died, including 28% of the acetaminophen group. The authors concluded that most cases of liver injury in the United States are due to medications and may be preventable.

Findings in children

THE FDA LOOKS AT THE PROBLEM

Why overdoses occur

A recent FDA report²² cited the following reasons for acetaminophen overdose:

Some patients may experience liver injury at doses only slightly above the recommended 4-g daily limit.
Some patients may be more prone to liver injury from acetaminophen.
The symptoms associated with liver injury due to acetaminophen can be nonspecific and tend to evolve over several days.
Many acetaminophen-containing products are available, including over-the-counter and prescription drugs with many different strengths and indications.
Consumers are unaware of the risk of liver toxicity with acetaminophen.
Prescription products are not always clearly labeled with acetaminophen as an ingredient.
Pediatric dosage forms are available in many different concentrations.

New package labeling

In view of this information, the FDA has mandated new labeling for acetaminophencontaining products (Table 3).²²

Recommendations from an advisory panel

THE UNITED KINGDOM ACTED IN 1998

SUMMARY

References

Burke A, Smyth EM, Fitzgerald GA. Analgesic-antipyretic agents: pharmacotherapy of gout. In:Brunton LL, Lazo JS, Parker K, editors. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill, 2006:671–716.
Bronstein AC, Spyker DA, Cantilena LR, Green J, Rumack BH, Heard SE. 2006 Annual Report of the American Association of Poison Control Centers National Poison Data System (NPDS). Clin Toxicol (Phila) 2007; 45:815–917.
Schwartz J, Stravitz T, Lee WM; American Association for the Study of Liver Disease Study Group. AASLD position on acetaminophen. www.aasld.org/about/publicpolicy/Documents/Public%2520Policy%2520Documents/AcetaminophenPosition.pdf.
Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Populationbased surveillance for acute liver failure. Am J Gastroenterol 2007; 102:2459–2463.
Institute for Safe Medication Practices. How are you preventing acetaminophen overdoses? www.ismp.org/newsletters/acutecare/articles/20030808.asp. Accessed 11/17/2009.
Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11:525–548.
Tylenol package insert. Fort Washington, PA: McNeil-PPC Inc.; 1999.
Bizovi KE, Hendrickson RG. Chapter 34. Acetaminophen. In:Hoffman RS, Nelson LS, Howland MA, Lewin NA, Flomenbaum NE, Goldfrank LR, editors. Goldfrank’s Manual of Toxicologic Emergencies. 3rd ed. McGraw-Hill: New York, 2007. www.accessemergencymedicine.com/content.aspx?aID=88781. Accessed 11/7/2009.
Hung OL, Nelson LS. Chapter 171. Acetaminophen. In:Tintinalli JE, Kelen GD, Stapcynski S, editors. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 6th ed. McGraw-Hill: New York, 2004. www.accessmedicine.com/content.aspx?aID=602606. Accessed 11/17/2009.
Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296:87–93.
American Academy of Pediatrics Committee on Drugs. Acetaminophen toxicity in children. Pediatrics 2001; 108:1020–1024.
Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am 2008; 92:761–794.
Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359:285–292.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871–876.
Acetadote package insert. Nashville, TN: Cumberland Pharmaceuticals; 2008Dec.
Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41:1179–1197.
Product Information: acetylcysteine inhalation solution, acetylcysteine inhalation solution. Hospira,Inc, Lake Forest, IL, 2004.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.
Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954.
Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372.
Squires RH, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the Pediatric Acute Liver Failure Study Group. J Pediatr 2006; 148:652–658.
US Food and Drug Administration. Questions and answers on final rule for labeling changes to over-the-counter pain relievers. www.fda.gov/Drugs/NewsEvents/ucm144068.htm. Accessed 10/30/2009.
Perrone M. FDA panel recommends smaller doses of painkillers. Associated Press. Adelphi, MD. June 30, 2009.
Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ 2004; 329:1076.
Hughes B, Durran A, Langford NJ, Mutimer D. Paracetamol poisoning—impact of pack size restrictions. J Clin Pharmacol Ther 2003; 28:307–310.
Wilkinson S, Taylor G, Templeton L, Mistral W, Salter E, Bennett P. Admissions to hospital for deliberate self-harm in England 1995–2000: an analysis of hospital episode statistics. J Public Health Med 2002; 24:179–183.
Greene SL, Dargan PI, Leman P, Jones AL. Paracetamol availability and recent changes in paracetamol poisoning: is the 1998 legislation limiting availability of paracetamol being followed? Postgrad Med J 2006; 82:520–523.

References

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Schwartz J, Stravitz T, Lee WM; American Association for the Study of Liver Disease Study Group. AASLD position on acetaminophen. www.aasld.org/about/publicpolicy/Documents/Public%2520Policy%2520Documents/AcetaminophenPosition.pdf.
Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Populationbased surveillance for acute liver failure. Am J Gastroenterol 2007; 102:2459–2463.
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Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007; 11:525–548.
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Hung OL, Nelson LS. Chapter 171. Acetaminophen. In:Tintinalli JE, Kelen GD, Stapcynski S, editors. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 6th ed. McGraw-Hill: New York, 2004. www.accessmedicine.com/content.aspx?aID=602606. Accessed 11/17/2009.
Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296:87–93.
American Academy of Pediatrics Committee on Drugs. Acetaminophen toxicity in children. Pediatrics 2001; 108:1020–1024.
Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am 2008; 92:761–794.
Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359:285–292.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871–876.
Acetadote package insert. Nashville, TN: Cumberland Pharmaceuticals; 2008Dec.
Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41:1179–1197.
Product Information: acetylcysteine inhalation solution, acetylcysteine inhalation solution. Hospira,Inc, Lake Forest, IL, 2004.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445.
Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954.
Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364–1372.
Squires RH, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the Pediatric Acute Liver Failure Study Group. J Pediatr 2006; 148:652–658.
US Food and Drug Administration. Questions and answers on final rule for labeling changes to over-the-counter pain relievers. www.fda.gov/Drugs/NewsEvents/ucm144068.htm. Accessed 10/30/2009.
Perrone M. FDA panel recommends smaller doses of painkillers. Associated Press. Adelphi, MD. June 30, 2009.
Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ 2004; 329:1076.
Hughes B, Durran A, Langford NJ, Mutimer D. Paracetamol poisoning—impact of pack size restrictions. J Clin Pharmacol Ther 2003; 28:307–310.
Wilkinson S, Taylor G, Templeton L, Mistral W, Salter E, Bennett P. Admissions to hospital for deliberate self-harm in England 1995–2000: an analysis of hospital episode statistics. J Public Health Med 2002; 24:179–183.
Greene SL, Dargan PI, Leman P, Jones AL. Paracetamol availability and recent changes in paracetamol poisoning: is the 1998 legislation limiting availability of paracetamol being followed? Postgrad Med J 2006; 82:520–523.

Issue

Cleveland Clinic Journal of Medicine - 77(1)

Issue

Cleveland Clinic Journal of Medicine - 77(1)

Page Number

19-27

Page Number

19-27

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Publications

Topics

Drug Therapy

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Article

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Acetaminophen: Old drug, new warnings

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Acetaminophen: Old drug, new warnings

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KEY POINTS

Acetaminophen is the leading cause of acute liver failure in the United States, and nearly half of acetaminophenassociated cases are due to unintentional overdose.
In many cases of unintentional overdose, patients took more than one acetaminophen-containing product and did not know that both products contained this drug.
Prescribers need to inform all patients, especially vulnerable ones (eg, those taking enzyme-inducing drugs, those who chronically use alcohol, and those who are malnourished) of the risks associated with acetaminophen.
Although no consensus has been reached on what is a safe dose in patients with liver disease, 4 g/day is too much: a total daily dose of no more than 2 g is recommended to decrease the risk of toxicity in these patients.

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