P&T News: October 1999

Atorvastatin: A Review of Its Pharmacology and Place in Therapy

Beth Bryles Phillips, Pharm.D., BCPS, Clinical Pharmacy Specialist, Department of Pharmaceutical Care
Peer Review Status: Internally Peer Reviewed by Howard R. Knapp, M.D., Professor and Director of Clinical Pharmacology, Department of Internal Medicine

Atorvastatin (Lipitor[R], Parke-Davis) is a relatively new synthetic HMG-CoA reductase inhibitor indicated for the treatment of hyperlipidemia in patients with primary hypercholesterolemia, mixed dyslipidemia, and familial hypercholesterolemia.1 Prior to the addition of atorvastatin to the market, simvastatin was the most potent agent available. A 10 mg dose of atorvastatin given once daily may provide a 35 to 41% lowering of LDL cholesterol.'"' In contrast, a 10 mg dose of simvastatin given once daily provides a 30 to 33% lowering in LDL cholesterol. 10,11 Additionally, atorvastatin may lower triglycerides by as much as 46% in patients with very high triglycerides. 14

Pharmacokinetic Parameters, Metabolism, and Dosing
With minor differences, atorvastatin exhibits similar pharmacologic characteristics as other statins. Atorvastatin is rapidly absorbed as peak plasma concentrations are seen within two hours after administration.9 Although ingestion with food has been shown to decrease both the extent and rate of atorvastatin absorption, this effect does not seem to be clinically significant. The LDL-lowering effects of atorvastatin are comparable when the drug is administered with or without food." Because atorvastatin undergoes extensive hepatic first-pass metabolism, the systemic bioavailability is relatively low at only 12%. However, atorvastatin is metabolized by cytochrome P450 3A4 into several active metabolites. These metabolites are responsible for approximately 70% of the HMG-CoA reductase inhibition.

Unlike other statins which have been shown to be most effective when administered in the evening , atorvastatin produces similar reductions in LDL cholesterol when administered without regard to the time of day or meals. Since excretion is primarily in the bile and only a very small portion of each dose is eliminated renally, no dosing adjustments are required in patients with renal insufficiency. Due to the potential for hepatic transaminase elevation, atorvastatin is generally not recommended for use in patients with hepatic dysfunction.9

Clinical Trials
Since atorvastatin was first marketed in the United States in 1996, there have been several clinical trials published evaluating the effects of atorvastatin on various lipoproteins. 10-12,14,16-18 Although many of the trials are short-term, three trials have evaluated the efficacy of atorvastatin for one year. 16-18 A summary of clinical trials evaluating the efficacy of atorvastatin compared to placebo can be found in Table 1, and trials comparing atorvastatin with other statins can be found in Table 2. As shown in Tables I and 2, the statins produced dosedependent decreases in LDL cholesterol. Atorvastatin achieved significantly more reduction in LDL cholesterol and triglycerides than the other agents studied. In many cases, 10 mg of atorvastatin produced more LDL-lowering effects than 40 mg of fluvastatin, lovastatin, or pravastatin.

Table 1. Lipid-lowering Effects of Atorvastatin When Compared with Placebo

Study	Design	Duration	Patient Population	Treatment/Daily Dose (no. patients)	Mean % Change from Baseline
					TC	LDL	HDL	TG
Nawrocki et al11	R, DB PC	6 weeks	79 patients with LDL 160 to 240 mg/dl and TG < 300 mg/dl	Placebo (12) A 2.5 mg (11) A 5 mg (13) A 10 mg (11) A 20 mg (10) A 40 mg (11) A 80 mg (11)	5 -17* -22* -30* -35* -38* -46*	8 -25* -29* -41 * -44* -50* -61*	-3 5 8 5 12* -3 3	-1 -10 -25* -14 -33* -25* -27*
Heinonen et al12	R, DB, PC	26 weeks	35 patients with LDL > 160 mg/dl and TG < 400 mg/dl	Placebo (17) A 10 mg (18)	2 -26*	1 -35*	-1 3*	14 -21
Bakker-Arkema et al14	R, DB, PC MC	4 weeks	55 patients with mean LDL 119 mg/dl and mean TG 603 mg/dl	Placebo (14) A 5 mg (13) A 20 mg (16) A 80 mg (12)	-1 -21 -32* -43 *	- 1 -17* -33* -41 *	4 9 13* 12	-9 -27 -32* -46*
A=Atorvastatin DB=Double-blind			MC=Multi-center PC=Placebo-controlled			R=Randomized * p< 0.05 compared to placebo

Recently, the effects of Atorvastatin on HDL cholesterol have come into question. In a recent 12-week, openlabel, industry-sponsored trial, the lipid-lowering effects of simvastatin 40 and 80 mg were compared to atorvastatin 20 and 40 mg. 19 Although decreases in LDL cholesterol and triglycerides were similar to the results of other trials, simvastatin 40 and 80 mg increased HDL cholesterol more than atorvastatin 20 and 40 mg, 6.7 and 6.6% vs. 4.0 and 3.0%, respectively (p<0.05). It has been postulated that atorvastatin may have a prolonged inhibition of cholesterol biosynthesis compared to other statins resulting in smaller increases in HDL due to its long half-life. Although this finding was statistically significant, the absolute difference is small and the clinical significance of these data is unknown. In the conclusion, the authors suggest more studies must be completed to determine if this variance in HDL cholesterol would impact cardiovascular outcomes.

Table 2. Comparative Trials Evaluating Atorvastatin with Other HMG-CoA Reductase Inhibitors

Study	Design	Duration	Patient Population	Treatment / Daily Dose (no. patients)	% Change from Baseline
					TC	LDL	HDL	TG
Bertolini et al 16	R, DB, MC	52 weeks	288 patients with Fredrickson type Ila and Ilb hyperlipidemia	A 10 to 20 mg (214) P 20 to 40 mg (74)	-25* -16	-35* -23	7 10	-14* -3
Dart et al 17	R, DB, MC	52 weeks	173 patients with elevated LDL cholesterol	A 10 to 20 mg (129) S 10 to 20 mg (44)	-30** -25	-38** -33	7 7	-16** -8
Davidson et al18	R, DB, MC	52 weeks	970 patients with primary hypercholesterolemia	A 10 to 20 mg (731) L 20 to 40 mg (239)	-27*** -21	-37*** -29	7 7	-16*** -8
Jones et al (CURVES study)10	R, OL, MC	8 weeks	518 patients with LDL > 160 mg/dl	A 10 mg (73) P 10 mg (14) S 10 mg (70)	-28**** -13 -21	-38**** -19 -28	6 10 7	-13 3 -12
				A 20 mg (51) P 20 mg (41) S 20 mg (49) F 20 mg (12) L 20 mg (16)	-35**** -18 -26 -13 -21	-46**** -24 -35 -17 -29	5 3 5 1 7	-20 -15 -17 -5 -12
				A 40 mg (61) P 40 mg (25) S 40 mg (61) F 40 mg (12) L 40 mg (16)	-40**** -24 -30 -19 -23	-51**** -34 -41 -23 -31	5 6 10 -3 5	-32**** -10 -15 -13 -2
				A 80 mg (10) L 80 mg (11)	-42 -36	-54 -48	-0.1 8	-25 -13
R=Randomized DB=Double-Blind MC=Multi-Center OL=Open-Label		A=Atorvastatin F=Fluvastatin L=Lovastatin P=Pravastatin S=Simvastatin		*p<0.05 compared to pravastatin **p<0.05 compared to simvastatin ***p<0.05 compared to lovastatin ****p<0.05 atorvastatin compared to the other groups

To date, atorvastatin has not been evaluated in long-term trials to determine its effect on cardiovascular outcomes, such as incidence of myocardial infarction and mortality. Other trials using simvastatin and pravastatin have shown improvement in cardiovascular morbidity and mortality.2,3,7,8 1 The results of these trials suggest that the improvements in cardiovascular morbidity and mortality are a class effect of the statins.

Because statins decrease LDL cholesterol and possibly triglycerides in a dose-dependent manner, it has been postulated that other statins may produce similar reductions to atorvastatin in LDL cholesterol and triglycerides if these agents are administered at higher than currently recommended doses. One study investigating the cholesterol lowering effects of simvastatin at high doses (40 to 160 mg) was recently conducted .21 Although simvastatin produced median reductions of up to 53% in LDL cholesterol and 33% in triglycerides, there was a large percentage of patients who did not respond as favorably. One case of myopathy and several cases of elevated hepatic transaminases were noted in patients receiving simvastatin at higher than currently recommended doses (i.e., 160 mg).20 A similar trial with pravastatin is currently being conducted. Comparative trials and dose-safety issues within the HMGCoA reductase inhibitor class need to be addressed before higher doses of these statins can be routinely recommended.

Adverse Effects Like other statins, atorvastatin is generally well tolerated. A summary of the commonly reported adverse effects in clinical trials is included in Table 3. Overall, less than 2% of patients enrolled in clinical trials 21 withdrew due to adverse reactions. Of specific concern with all statins is the effect on hepatic transaminases. Elevations of more than three times upper limit normal (ULN) have been reported by the manufacturer in an average of 0.7% of patients receiving atorvastatin therapy.21 The incidence seems to be lowest with the 10 mg daily dose of atorvastatin (0.2%) as compared to the 80 mg daily dose (2.3%).21 In comparison, the Expanded Clinical Evaluation of Lovastatin (EXCEL) study evaluated the effect of 20 to 80 mg of lovastatin daily on 8245 22 men and women for 48 weeks. Elevations in hepatic transaminases greater than three times ULN were found in 0. 1% of patients receiving 20 mg daily, compared to 1.5% patients in the 80 mg group.

Table 3. Common Adverse Events Reported in Atorvastatin Clinical Trials (N=2502) 19
Adverse Event	Patients Experiencing Events (%)
Constipation	3
Flatulence	2
Dyspepsia	2
Abdominal pain	2
Headache	1
Myalgia	1
Any event	20

Drug Interactions
Because atorvastatin is metabolized by cytochrome P450 3A4, any agent that induces or inhibits this hepatic enzyme has the potential to interact with atorvastatin. Relatively few drug interactions have been reported for atorvastatin. This is likely due to the fact atorvastatin has only been available for a short period of time when compared to lovastatin. A summary of drug interactions can be found in Table 4.

Table 4. Drug Interactions Associated with Atorvastatin Therapy
Interacting Medication	Effect	Clinical Significance
Azole antifungal agents	increased atorvastatin concentrations due to inhibition of CYP3A4	May increase risk of myopathy or rhabdomyolysis
Combination oral contraceptives (Ethinyl estradiol/ norethindrone)	increased AUC of ethinyl estradiol by 20%, norethindrone by 30%	Unknown; monitor more frequently for hormonal adverse effects or consider using another form of contraception
Digoxin	increased digoxin concentrations by 20%	May require adjustment in digoxin dose; monitor for efficacy, signs/symptoms digoxin toxicity, and digoxin levels
Erythromycin	increased atorvastatin concentrations by 40% due to inhibition of CYP3A4	May increase risk of myopathy or rhabdomyolysis
Nefazodone	increased atorvastatin concentrations due to inhibition of CYP3A4	May increase risk of myopathy or rhabdomyolysis
Warfarin	no effect	May be used concurrently with atorvastatin without concern
AUC = area under the curve

Probably the most worrisome adverse event associated with the statins is myopathy and rhabdomyolysis. These adverse events occur at a much higher rate if drug interactions are present. Agents which have been associated with an increased risk of myopathy when administered concurrently with statins include erythromycin, cyclosporine, fibric acid derivatives (e.g., bezafibrate, clofibrate, gernfibrozil), niacin, and azole antifungal agents (e.g., ketoconazole, fluconazole, and itraconazole). These agents should be administered concurrently with statins with extreme caution, if at all. Despite the fact these complications have not been reported with atorvastatin, the potential still exists. It is recommended that the same precautions for other statins be followed with atorvastatin.' In addition, discontinuation of atorvastatin therapy is recommended in patients who complain of diffuse myalgias, muscle weakness, and/or experience significant increases in creatine kinase levels.' Post-marketing surveillance of adverse drug reactions may be a key factor in determining the overall safety of long-term atorvastatin therapy.

Place in Therapy
Atorvastatin provides significant reductions in LDL cholesterol (as much as 60% at the maximum dose) and may produce large reductions in triglycerides in those patients with hypertriglyceridemia. One potential advantage of atorvastatin is its use as monotherapy for patients whose LDL cholesterol previously necessitated multiple- drug therapy to attain their target cholesterol value. Atorvastatin may also be used in those patients with elevated LDL cholesterol and triglyceride values who have a contraindication to niacin therapy (e.g., diabetes mellitus or gout) or in whom niacin therapy failed to achieve adequate reductions in LDL cholesterol. Although fluvastatin is still the most cost-effective statin for patients who do not require a large reduction in LDL cholesterol, atorvastatin may be a good choice in those patients who require more than a 25% reduction in LDL cholesterol. Because the 10 mg dose of atorvastatin lowers LDL cholesterol 35 to 41%, atorvastatin may be more cost effective than using other statins in higher doses. Table 5 summarizes dosing and administration guidelines for the available statins and provides cost comparison information.

Table 5. Comparison of HMG-CoA Reductase Inhibitors
Drug	Dose per Day	Effect on LDL-C	Effect on HDL-C %	Effect on TG %	Dosage Time	Average Wholesale Price (AWP) per Month	AWP Yearly Cost / % LDL decrease
Atorvastatin*	10 mg 20 mg 40 mg 80 mg (40 mg x 2)	-39 -43 -50 -60	+6 +9 +6 +5	-19 -26 -29 -37	Anytime of day	$55 $85 $102 $204	$17 $24 $25 $42
Cerivastatin	0.2 mg 0.3 mg 0.4 mg	-25 -28 -34	+9 +10 +7	-16 -13 -16	Bedtime	$43 $43 $43	$21 $18 $15
Fluvastatin*	20 mg 40 mg 40 mg BID	-22 -25 -32	+2.9 +3.7 +4	-7 -10 -12	Bedtime	$38 $42 $84	$21 $18 $29
Lovastatin	20 mg 40 mg 80 mg (40 mg x 2)	-29 -31 -48	+7 +5 +8	-12 -2 -13	Evening meal	$70 $126 $252	$30 $51 $66
Pravastatin*	10 mg 20 mg 40 mg	-22 -32 -34	+7 +2 +12	-15 -11 -24	Bedtime	$60 $65 $106	$34 $26 $40
Simvastatin*	10 mg 20 mg 40 mg 80 mg	-33 -33 -40 -47	+9 +11 +12 +8	-10 -19 -19 -24	Bedtime	$63 $110 $110 $110	$24 $41 $34 $28
* denotes UIHC formulary items AWP=Average Wholesale Price

Summary
Although data demonstrating its long-term impact on morbidity and mortality are lacking, atorvastatin does provide potent reductions in LDL cholesterol and triglycerides. The adverse effect profile (when used at daily doses less than 80 mg) is comparable to currently available agents. In addition, atorvastatin is a cost-effective agent for patients who require large reductions in LDL cholesterol. Further studies must be conducted to determine whether differences in HDL cholesterol are clinically relevant. Due to the increased incidence of hepatic transaminase elevation associated with maximum doses of atorvastatin, patients using the 80 mg dose should be monitored more closely.

References

1. NIH Publication No. 93-3095, September 1993.
2. Lancet. 1994;344:1383-9.
3. N Engl J Med. 1995;333:1301-7.
4. JAMA. 1984;251:365-74.
5. N Engl J Med. 1987;317:1237-45.
6. Circulation. 1995;91:2274-2282.
7. N Engl J Med 1998;339:1349-57.
8.NEnglJMed 1996;335:1001-9.
9. Parke-Davis. Lipitor package insert. Morris Plains, NJ: 1996.
10. Am J Cardiol 1998;81:582-7.
11. Arterioseler Thromb Vasc Biol. 1995; 15:678-82.
12. Clin Ther 1996;18:853-63.
13. Merck, Sharp, & Dohme. Zocor package insert. West Point, PA: 199 1.
14. JAMA. 1996;275:128-33.
15. J Clin Pharmacol. 1995;35:990-4.
16. Atherosclerosis. 1997;130:191-7.
17. Am J Cardiol. 1997;80:39-44.
18. Am J Cardiol. 1997;79:1475-8 1.
19. Am J Cardiol. 1999;83:1776-7.
20. Am J Cardiol. 1997;79:38-42.
21. Arch Intern Med. 1998; 158:577-84.
22. Am JMed. 1991;91 (Supplement 113):25S-30S.

DRUGS ADDED TO STOCK

CILOSTAZOL Tablets: 100 mg Cilostazol (Pletal[R] Pharmacia & Upjohn) is indicated for the reduction of symptoms of intermittent claudication. It is contraindicated in patients with any degree of heart failure.

ETANERCEPT Injection: 25 mg vial Etanercept (Enbrel[R] - Wyeth-Ayerst) is a recombinant tumor necrosis factor (TNF) receptor indicated for moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to disease-modifying antirheumatic drugs. Etanercept therapy should not be initiated or continued in patients with active infections. NOTE: The patient's initial prescription must be signed by staff from the Division of Rheumatology.

PROCAINE Injection: 10% Procaine (Novocain[R] - Sanofi Winthrop) is an anesthetic agent. The 10% concentration is indicated for spinal anesthesia.

TOLTERODINE Tablets: 1 mg, 2 mg Tolterodine (Detrol[R] - Pharmacia & Upjohn) tablets are indicated for the treatment of overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence.

ADDITIONAL ACTIONS

LAMOTRIGINE (LAMICTAL[R]) CHEWABLE TABLETS A 25 mg chewable tablet has been added to stock.

OXYCODONE ORAL SOLUTION A 20 mg per ml oral solution has been added to stock.

Note: The cost lowing each brief monograph is the UIHC acquisition

DRUGS DELETED FROM STOCK

DYCLONINE TOPICAL SOLUTION The 0.5% and 1% topical solutions have been discontinued by all manufacturers. Tetracaine and benzocaine topical solutions are available.

LIDOCAINE TOPICAL SPRAY The 10% spray has been discontinued by all manufacturers. Tetracaine and benzocaine topical solutions are available.

Previous Page | Title Page