P&T News: November 1995, Vol. 16, No. 5

The HMG-CoA Reductase Inhibitors

Jane C. Blayney, Pharm.D.
Peer Review Status: Internally Peer Reviewed by David A Chappell, M.D., Associate Professor, Division of Cardiovascular Diseases, Department of Internal Medicine

Due to the significant differences in cost among the HMG-CoA reductase inhibitors, a careful review of these agents was recently undertaken in order to make available the most cost-effective agents with proven clinical benefit. Based on this review, the HMG-CoA reductase inhibitors have been designated by the Pharmacy and Therapeutics Subcommittee to be therapeutically equivalent and interchangeable for most indications. Given the similar efficacy of pravastatin, simvastatin, and lovastatin and the reduced costs for fluvastatin, the following agents will be stocked at UIHC: pravastatin, simvastatin, and fluvastatin. Lovastatin will be removed from stock effective January 1, 1996.

The following review will discuss the comparative efficacy, side effects, and drug interactions of these agents.

Pharmacology/Pharmacokinetic Properties/Dosing
The HMG-CoA reductase inhibitors are indicated as an adjunct to dietary management, exercise, and weight reduction to reduce elevated TC and LDL-C in patients with familial hypercholesterolemia (Types IIA & IIB) when nonpharmacologic measures have proven inadequate.4 These agents inhibit cholesterol synthesis in the liver, which leads to a compensatory increase in the production of the LDL receptors and increased catabolism of both LDL and some of its precursors.5 Efficacy of all HMG-CoA reductase inhibitors as monotherapies in lowering TC and LDL-C in the treatment of primary hypercholesterolemia has been demonstrated in placebo-controlled trials. At usual therapeutic doses, these agents decrease TC by 15 to 30%, LDL-C by 20 to 40%, and triglycerides by 10 to 20%; HDL-C is increased by 5 to 10%.6 It should be noted that bile acid sequestrants and niacin also play a significant clinical role in cholesterol reduction. However, the HMG-CoA reductase inhibitors are more potent agents.

Three of the HMG-CoA reductase inhibitors are fungal metabolites or derivatives thereof - lovastatin, pravastatin, and simvastatin; fluvastatin is totally synthetic.7 Lovastatin and simvastatin are administered as prodrugs, while fluvastatin and pravastatin are administered as active agents. Both fluvastatin and pravastatin are more hydrophilic than simvastatin or lovastatin. Table 1 summarizes the pharmacokinetic differences of HMG-CoA reductase inhibitors. Although these agents have pharmacokinetic differences, the clinical implications are not widely apparent and these agents are therapeutically interchangeable for most indications.7

Table 1. Pharmacokinetic Profiles of the HMG-CoA Reductase Inhibitors[8]
Properties	Fluvastatin	Lovastatin	Pravastatin	Simvastatin
Prodrug	No	Yes	No	Yes
Crosses blood-brain barrier	No	Yes	No	Yes
Liver excretion, % of absorbed dose	95	70	50	less than 87
Protein binding %	98	95	45	95
Effect of food on absorption	No	Yes	No	No
Lipid solubility	Hydrophilic	Lipophilic	Hydrophilic	Lipophilic

There are small differences in the absolute percentage decreases in TC and LDL-C and/or increase in HDL-C reported for the same dose of different agents; however, these differences are clinically insignificant for patients requiring mild to moderate reduction in LDL-C.9 These agents are competitive inhibitors of HMG-CoA reductase, thus the dose-response curve for decreasing LDL-C as a function of the daily dose is non-linear, and the largest reductions in LDL-C per milligram of drug occur with the lowest dose.10 These drugs are administered once daily in the evening. With the exception of lovastatin, they may be given without regard to meals. This is a potential compliance issue with lovastatin. With all statin agents dosage adjustments should be made according to patient response, but not more often than at four-week intervals in order to adequately assess response. Each agent undergoes extensive hepatic metabolism and should be used with caution in patients with hepatic dysfunction. No dosage changes are recommended for patients with impaired renal function. Table 2 summarizes the mean changes in lipoproteins, dosing, and cost information for the HMG-CoA reductase inhibitors.

Comparative Efficacy
There have been many clinical trials comparing lovastatin, pravastatin, and simvastatin. Based on the results from these trials, lovastatin and pravastatin are approximately equipotent on a milligram-per-milligram basis in lowering TC and LDL-C, whereas simvastatin appears to be at least twice as potent as lovastatin and pravastatin.7 Lovastatin, pravastatin, and simvastatin have demonstrated a capability to cause atherosclerotic regression. When administered as monotherapy, these three agents also have been shown to reduce coronary mortality.2s3sl3 Fluvastatin has not yet been tested as an agent to induce atherosclerotic regression; however, because the mechanism of action of lipid lowering is a class effect, fluvastatin in theory should also decrease CHD morbidity and mortality.

The Scandinavian Simvastatin Survival Study (4S) randomized M44 men and women between 35 and 70 years of age who had coronary heart disease and plasma total cholesterol concentrations of 212 to 310 mg/dl to receive simvastatin or placebo.2 The study showed a 30% reduction in total mortality in patients followed for a median duration of 5.4 years and a 42% decrease in death from coronary heart disease. Simvastatin reduced the risk of experiencing major coronary events by 34%, hospital-verified non-fatal myocardial infarction (MI) by 37%, and the need for coronary artery bypass grafting or percutaneous transluminal coronary angioplasty by 37 % . The drug treatment led to a mean reduction in LDL-C of 35 % and triglycerides of 10% and an increase in HDL-C of 8%. This study provides the most convincing evidence on the beneficial effects of the HMG-CoA reductase inhibitors on coronary mortality in patients with pre-existing CHD.

Table 2. Dosing, Lipoprotein Changes, and Costs of the HMG-CoA Reductase Inhibitors7,11-13
Agent	Fluvastatin Initial Maximum	Lovastatin Initial Maximum	Pravastatin Initial Maximum	Simvastatin Initial Maximum
Equivalent Dosing Range (Initial and Maximum Dose)	20 mg 40 mg	20 mg 80 mg	20 mg 40 mg	10 mg 40 mg
Mean Changes in LDL-C	-21 -25	-24 -40	-22 -34	-24 -40
Mean Change in TG	-7 -10	-10 -19	-15 -24	-10 -19
Mean Change in HDL-C	+2 +8	+7 +10	+9 +12	+7 +12
LDL-C = Low density liprotein cholesterol TG = Triglycerides HDL-C = High density liportein cholesterol

The Pravastatin, Lipids, and Atherosclerosis in the Carotids (PLAC II) trial showed a 60% reduction in coronary events with pravastatin treatment.3 This trial was a three-year, double-blind trial which randomized 151 patients with mild to moderate hyperlipidemia to receive either pravastatin or placebo. The progression of early extracranial carotid atherosclerosis was the primary endpoint. Results showed no significant differences (p=0.44) seen in the carotid bifurcation, internal carotid artery, or all segments combined (the primary endpoint); however, pravastatin did reduce the increase in wall thickness in the common carotid artery (p=0.02). Cardiac event rates were reduced in the pravastatin treatment group for two combined endpoints: nonfatal or fatal MI (13.3 % for placebo versus 2.7 % pravastatin, p=0.018); and non-fatal MI or all deaths (17.1 % for placebo versus 6.7 % for pravastatin, p=0.049).

Fluvastatin is the newest agent to be released in the market. Its has been shown to effectively lower LDL-C by 21 to 25%, produces fewer side effects and drug interactions, and costs less when compared to therapy with other HMG-CoA reductase inhibitors.14 However, there have been no published studies proving that fluvastatin can induce atherosclerotic regression or decrease CHD morbidity and mortality. Fluvastatin alone does not have the ability to lower LDL-C by more than 25%, making it a less attractive alternative in patients with LDL-C levels greater than 140 mg/dl. However, when fluvastatin is combined with other lipid lowering agents like cholestyramine or niacin, it has been shown to decrease LDL-C by 32 to 40 % . '5 l6

Safety Evaluation
Clinical trials evaluating the comparative efficacy and safety of the HMG-CoA reductase inhibitors revealed similar safety and tolerability profiles for all agents. The relative rates of adverse events derived from product labeling are listed in Table 3. The most common side effects involve mild gastrointestinal distress (e.g., nausea, abdominal pain, diarrhea, constipation).6 Headache, fatigue, pruritus, and myalgia are other minor side effects that seldom prompt treatment termination. Mild transient elevations in liver enzymes have been reported with all the HMG-CoA reductase inhibitors. Hepatotoxicity occurs in approximately 1 % of the patients, and this adverse effect is clearly related to the dose of drug.6sl3 Routine monitoring of transaminase levels is recommended to screen for hepatotoxicity. All agents require a baseline analysis of liver function tests and additional monitoring at week 6 and week 12 of therapy. Thereafter, the recommended monitoring frequency for fluvastatin is at six-month intervals.17 For other agents, it is recommended that liver function be monitored at eight-week intervals for the next 32 weeks before the monitoring frequency is relaxed to approximately every six months.llsl2

Myopathy, with muscle tenderness and weakness, and serum creatine kinase elevations greater than ten times the upper limit of normal, is a rare but potentially serious adverse effect of the HMG-CoA reductase inhibitors.l8 In the Expanded Clinical Evaluation of Lovastatin (EXCEL) study of 8000 patients, myositis occurred in five lovastatin-treated patients.l9 In other large controlled clinical trials, one case has occurred with pravastatin,20 and two cases with simvastatin.21 To date, there has been no report of drug-related myopathy associated with fluvastatin.6

Table 3. Incidence of Adverse Effects with HMG-CoA Reducatase Inhibitors[22]
Adverse Effect	Lovastatin (%)	Simvastatin (%)	Pravastatin (%)	Fluvastatin (%)
Gastrointestinal:
Abdominal pain	5.7	3.2	5.4	5.5
Constipation	4.9	2.3	4.0	2.6
Diarrhea	5.5	1.9	6.2	6.0
Dyspepsia	3.9	1.1	2.9	8.1
Flatulence	6.4	1.9	3.3	2.6
Nausea	4.7	1.3	7.3	3.2
Musculoskeletal:
Myalgia	2.4	NR	2.7	3.4
Other:
Headache	9.3	3.5	6.2	8.7
Rash, pruritus	5.2	NR	4.0	2.7
__________ NR = Not reported

Drug Interactions
The major drug interactions seen with the HMG-CoA reductase inhibitors are listed in Table 4.23 Overall, there appear to be fewer drug interactions with fluvastatin and pravastatin as compared to their more hydrophobic counterparts, lovastatin and simvastatin. The primary concern regarding drug interactions is the possible increased risk of myopathy associated with using these agents concurrently with cyclosporine, gemfibrozil, erythromycin, or niacin.23 Concomitant therapy with these agents is generally not recommended. In post-transplant patients receiving cyclosporine, there is more extensive experience with the use of pravastatin therapy which has been shown to result in a low frequency of myopathy. If combination therapy with an immunosuppressant is warranted: 1) the dose of pravastatin should not exceed 20 mg daily; or 2) simvastatin should be initiated at 5 mg daily with a maximum dose of 10 mg daily. To date there is no evidence of myopathy reported with fluvastatin or pravastatin when combined with cyclosporine. Combinations of lovastatin or simvastatin with warfarin have been shown to prolong the prothrombin time and may increase the likelihood of bleeding; this has not been found with pravastatin or fluvastatin.5 23

Many patients with CHD have LDL-C > 190 mg/dl. Therefore, even a 45 % reduction in LDL-C, the maximum possible with monotherapy, will not permit patients with an LDL-C of > 190 mg/dl to reach a target of < 100 mg/dl as recommended by the current NCEP guidelines.4 These patients may require combination therapy. One treatment approach is the use of an HMG-CoA reductase inhibitor and niacin. Rhabdomyolysis with renal failure has been reported with lovastatin-niacin therapy.24 To date, myopathy during niacin combination therapy with either pravastatin or fluvastatin has not been reported. In one study of 158 hypercholesterolemic patients, pravastatin (40 mg/day) and niacin (2 g/day) reduced LDL-C by 43% (versus 16% on niacin monotherapy).20 Low-dose fluvastatin has achieved similar results when combined with niacin (3 g/day) in a randomized trial of 74 patients.25 Following nine weeks of therapy, LDL-C levels decreased 43.7% in the fluvastatin-niacin group, compared with 26.5% for niacin-placebo (p<0.001). In addition, HDL cholesterol rose by 33.1 % and triglycerides decreased by 32.3 % with the combination group.

Combination therapy with a fibrate derivative is another potentially effective combination but limited by the prospect of myopathy which has been reported when gemfibrozil is combined with lovastatin. The incidence of myopathy with the lovastatin-gemfibrozil combination ranges between 5 to 8 % . Myopathy has not been encountered upon administration of other HMG-CoA reductase inhibitors with gemfibrozil, and treatment with fluvastatin and bezafibrate (a fibrate derivative not yet available in the United States) did not prove myopathic.6,26

Table 4: Drug Interactions 5,6,23,26
DRUG	INTERACTING AGENT	PHYSIOLOGIC EFFECT
Lovastatin	Cyclosporine Erythromycin Niacin Warfarin	Increased risk of myositis/rhabdomyolysis Increased risk of myositis/rhabdomyolysis Increased risk of myositis/rhabdomyolysis Increased prothrombin time
Simvastatin	Warfarin	Increased prothrombin time
Fluvastatin	Cholestyramine	Decreased bioavailability of fluvastatin; separate administration by four hours
Pravastatin	Cholestyramine	Decreased bioavailability of pravastatin; separate administration by four hours
All "statins"	Gemfibrozil	Myopathy or rhabdomyolysis may occur

Conclusions
Since the annual cost of cardiovascular disease in the United States is now approximately $110 billion, aggressive cholesterol reduction is a cost-effective approach in the management of patients with coronary artery disease and hypercholesterolemia. The HMG-CoA reductase inhibitors are potent antilipidemic agents, and the efficacy of these agents has been demonstrated in both placebo-controlled and comparative trials with other antilipidemic agents. Many published trials have assessed the comparative efficacy of the HMG-CoA reductase inhibitors, but very few head-to-head comparisons of different agents have been completed. Also, the results of these studies are confounded by the use of nonequipotent doses of agents in this class. At doses that produce moderate reductions in LDL-C (Table 2), the major difference among these agents is cost. For these reasons, fluvastatin offers a therapeutic gain at a reduced cost in patients who require a 25% reduction or less in LDL-C. Pravastatin, simvastatin, and lovastatin should be reserved for patients with severe hypercholesterolemia or for patients refractory to other lipid-lowering agents.

References

1. Br Heart J. 1993; 69(Suppl):542-7.
2. Lancer. 1994; 344:1383-9.
3. Am J Cardiol. 1995; 75:455-9.
4. Circulation. 1994; 89:1333-445.
5. Hosp Form. 1994; 29:244-50.
6. Clin Cardiol. 1995; 18:307-15.
7. Ann Pharm. 1995; 29:743-59.
8. Clin Cardiol 1994; 17(Suppl lV):3-10, 21-7.
9. Drug Invest. 1993; 5:138-40.
10. Clin Ther. 1994; 16(1):2-24.
11. Bristol Myers Squibb. Pravachol package insert. Princeton, NJ:1994.
12. Merck Sharp Dohme. Zocor package insert. West Point, PA:l991 December.
13. Am J Card. 1994; 73:3D-llD.
14. Clin Card . 1994; 17(Suppl IV): 11-5.
15. Ann Intern Med. 1994; 120:537-43.
16. Clin Card. 1994; 17:32-3.
17. Sandoz. Lescol package insert. East Hanover, NJ: 1994.
18. JAMA 1990; 264:71-75.
19. Am JMed. 1994; 91:(Suppl):lB-25S.
20. Clin Ther. 1993; 15:57-64.
21. Am J Cardiol. 1991; 68:1127-31.
22. Olin B. ad. Facts & Comparisons. St. Louis: J.B. Lippencott; 1995
23. Hypolipidemic Drug Interaction. In: Hansten P. Horn J. eds. Drug Interactions Newsletter. Vancover: Applied Therapeutics; 1993:623-8.
24. Merck & Co. Mevacor package insert. West Point, PA: 1994.
25. Am J Card. 1994; 73(Suppl):D25-9.
26. Am J Card. 1994; 73(Suppl):D30-7.

As of November 1, 1995, all orders received for H2-RAs other than cimetidine will not be considered valid. When an order for an H2-RA other than cimetidine is received by Pharmacy, the prescriber will be verbally contacted to change the order to an equivalent dose of cimetidine. If the prescriber is unable to be reached, a copy of the zH2RA/ Cimetidine Conversion Form" (Form 649) will be placed on the front of the patient's chart. This form will alert the prescriber that the H2-RA order needs to be converted to an equivalent dose of cimetidine.

Famotidine will be available as a protocol drug and is to be prescribed only if a patient has experienced an adverse reaction to cimetidine, or if the individual has had a documented case of therapeutic failure with cimetidine. Ranitidine is no longer stocked. When a prescriber writes an order for famotidine, a "Famotidine Protocol Form" (Form 650) must be completed and signed by the prescriber. If famotidine is used for reasons other than the two criteria described below, the attending physician will also need to provide a signature and an explanation for the use of famotidine. The Famotidine Protocol Order Form lists the exception criteria needed to prescribe famotidine. The reverse side of the form provides equivalent dosing information, as well as comparative costs between cimetidine and famotidine dosing regimens.

If a prescriber deems famotidine to be medically necessary, he/she must check the appropriate exception on the protocol form, or provide a written explanation as to why cimetidine cannot be used. This form must be received by Pharmacy prior to dispensing famotidine. The Famotidine Protocol Form (Form 650) will contain the following exception criteria:

1) Patient has experienced an adverse reaction to cimetidine. This adverse reaction precludes the use of cimetidine in this patient.

2) Documented case of therapeutic failure with cimetidine.

The conversion of H2-receptor antagonist therapy to cimetidine will save UIHC in excess of $100,000 per year, and this savings will ultimately be realized by the patients receiving these agents, both while in the hospital and when returning to their community settings.

In order to aid prescribers with dosage conversions, an equivalent dosing chart for the H2receptor antagonists (l able 1, page 37) has been developed. Additional information regarding the H2-RAs, is available from Pharmacy satellites.

Table 1. H2-Receptor Antagonist Dosing Guidelines
Indication	Cimetidine	Famotidine	Nizatidine	Ranitidine
Acute therapy for active ulcers	800 mg PO qHS 400 mg PO BID 300 mg PO QID	40 mg PO qHS 20 mg PO BID	300 mg PO qHS 150 mg PO BID	300 mg PO qHS 150 mg PO BID
Maintenance therapy for ulcers	400 mg PO qHS	20 mg PO qHS	150 mg PO qHS	150 mg PO qHS
Gastroesophageal Reflux Disease (GERD)	400 mg PO BID*	20 mg PO BID 40 mg PO qHS	150 mg PO BID	150 mg PO BID
Erosive Esophagitis	400 mg PO QID 800 mg PO BID	20 to 40 mg PO BID	150 mg PO BID	150 mg PO QID
Pathological hypersecretory conditions	300 mg PO QID	20 mg PO QID		150 mg PO BID
Patient unable to take oral medication	300 mg IV q8hr 37.5 mg/hr IV continuous infuison	20 mg IV q12hr or 1.67 mg/hr IV continuous infusion	not available as IV	50 mg IV q8hr or 6.25 mg/hr IV continuous infusion
Prevention of upper GI bleeding	50 mg/hr IV continuous infusion or 300 mg IV q8h*	20 mg IV q12hr* or 1.67 to 3.4 mg/hr IV continuous infusion*		50 mg IV q8hr* or 6.25 mg/hr IV continuous infusion*
Pediatric dosing	20 to 40 mg/kg/day PO/IV divided q6hr*	1 to 1.2 mg/kg/day PO divided q8 to 12hr* 0.6 to 0.8 mg/kg/day IV divided q8 to 12hr*	nwot available in suspension or intravenous formulation	2 to 4 mg/kg/day PO divided q12hr8 1 to 2 mg/kg/day IV divided q6 to 8 hr*
Adjustments for renal impairments:
Crcl 10 to 50 ml/min	300 mg PO q12hr 300 mg IV q12hr	20 mg PO q12 to 24hr 20 mg IV q12 to 24hr	150 mg PO q24hr	150 mg PO q24hr 50 mg IV q12 to 24hr
CrCl less than 10 ml/min	300 mg PO q24hr 300 mg IV q24hr	20 mg PO q24 to 48hr 20mg IV q24 to 48hr	150 mg PO q48hr	150 mg PO q24hr 50 mg IV q24hr
__________ * literature supported

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Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

AMIODARONE Injection: 50 mg per ml Amiodarone (Cordarone(R) Wyeth-Ayerst) is a class m antiarrhythmic with electrophysiologic properties indicated for the treatment and prophylaxis of ventricular fibrillation and hemodynamically unstable ventricular tachycardia refractory to other therapy. NOTE: Amiodarone injection is restricted to prescribing by the Division of Cardiovascular Diseases.

ATOVAQUONE Suspension: 750 mg per 5 ml Atovaquone (Mepron(R) - Glaxo-Wellcome) suspension is indicated for the treatment of mild to moderate Pneumocystis canny pneumonia in patients unable to tolerate trimethoprim-sulfamethoxazole. NOTE: Atovaquone suspension has a twofold increase in bioavailability over the tablets. The dosing regimen for the suspension is 750 me twice daily with meals.

CYCLOSPORINE, MICROEMULSION Capsules: 25 mg, 100 mg Suspension: 100 me per ml Cyclosporine is an immunosuppressive agent indicated for the prophylaxis of organ rejection m kidney liver, and heart allogeneic transplants. The microemulsion formulation (Neoral(R) Sandoz) has improved absorption and a more consistent pharmacokinetic profile than the previously available formulation. NOTE: The two formulations are not bioequivalent and cannot be used interchangeably .

DOXAZOSIN Tablets: I mg, 2 mg 4 mg, 8 mg Doxazosin (Cardura(R) Roerig) is a selective alpha adrenergic antagonist indicated for the treatment of hypertension and the symptoms of benign prostatic hyperplasia.

ESTRADIOL Transdermal Patches: 0.05 mg and 0.1 mg per day Estradiol (Climara(R) - Berlex) transdermal patches provide estrogen replacement therapy. NOTE: The Climara(R) brand of estradiol transdermal parches is applied once-weekly; the Estraderm t brand of transdermal patches is applied twice-weekly.

FAMOTIDINE Tablets: 20 mg, 40 mg Suspension: 40 mg per 5 ml Injection: 20 mg per 50 ml in sodium chloride injection Famotidine (Pepcid(R) - Merck) is a histamine-2 receptor antagonist (ERA) indicated for the treatment of duodenal ulcer, gastric ulcer, gastroesophageal reflux disease, and pathological hypersecretory conditions. NOTE: Famotidine has been designated as a protocol drug by the Pharmacy and Therapeutics Subcommittee. Its use will be restricted to: I) parents who have experienced an adverse reaction to cimetidine; and 2) patients with documented therapeutic failure with cimetidine. If famotidine is deemed medically necessary for other indications, the protocol order form must be signed by the patient's attending physician.

LANSOPRAZOLE Capsules: 15 mg, 30 mg Lansoprazole (Prevacid(R) - TAP) is a proton pump inhibitor indicated for the treatment of active duodenal ulcer, erosive esophagitis, and pathological hypersecretory states.

MEGESTROL Suspension: 40 mg per ml The suspension form of megesterol is indicated for treatment of anorexia, cachexia, or significant weight loss in patients with AIDS.

MILRINONE Injection: I mg per ml Milrinone (Primacor(R) - Sanofi-Winthrop) is a positive inotrope and a vasodilator indicated for the short-term treatment of congestive heart failure.

VALACYCLOVIR Capsules: 500 mg Valacyclovir (Valtrex(R) Glaxo-Wellcome) is an antiviral agent indicated for the treatment of herpes zoster infections. It is less expensive and dosed less frequently than acyclovir when used for this indication.

Drugs Deleted From Stock

ATOVAQUONE TABLETS Discontinued by the manufacturer. Atovquone suspension is available.

ESTRADERM(R) This brand of estradiol transdermal patches has been replaced with the Climara(R) brand due to better adherence and fewer adverse skin reactions than Estraderm(R).

LOVASTATIN This deletion will become effective January 1, 1996. Fluvastatin, simvastatin, and pravastatin are available.

RANITIDINE Cimetidine is the primal H2RA available for use. Famotidine is available, if medically necessary, on a protocol basis.

We feel that this new name more accurately reflects the services provided.

H.J. Black
Director of Pharmaceutical Care

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