What does the pharmacist need to know to counsel patients about colesevelam?
Epidemiological studies have established that elevated levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipo-protein B (Apo B), as well as decreased levels of HDL-cholesterol (HDL-C), are associated with an increased risk of atherosclerosis and cardiovascular-related mortality. Furthermore, it has been documented through numerous trials that aggressive reduction of lipid levels can significantly reduce the risk of cardiovascular disease. It is estimated that more than 50 million Americans currently have at least mild elevations of cholesterol (hyper-cholesterolemia or Fredrickson Type IIa hyperlipidemia) and would benefit from some form of lipid-lowering therapy.
Diet and lifestyle changes generally represent the initial approach toward lipid reduction, but these often produce small and inconsistent results. For patients who continue to have elevated cholesterol levels following diet and lifestyle modifications, drug therapy is recommended. Currently available lipid-lowering drugs include the “statin” hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoARIs), the bile acid sequestrants, nicotinic acid, the fibric acids (gemfibrozil, clofibrate) and probucol. The lipid-lowering market is one of the fastest growing in the nation, generating over $6 billion in sales and nearly 95 million prescriptions over the past year.
For initial cholesterol-lowering therapy, the National Cholesterol Education Program (NCEP) recommends bile acid sequestrant drugs used alone or in combination with other drugs, such as the statin HMG-CoARIs. The safety and efficacy of cholestyramine resin and colestipol hydrochloride, the most commonly prescribed bile acid sequestrants, have been demonstrated repeatedly. These bile acid sequestrants alone reduce LDL-C concentrations by 10% to 30%. Combination therapy of bile acid sequestrants with niacin or an HMG-CoARI produces even larger LDL-C reductions of up to 60%.
Despite their proven efficacy and the lack of systemic effects resulting from nonabsorption from the gastrointestinal tract, the bile acid sequestrants currently available have a high drug discontinuation rate due, in large measure, to intolerable GI side effects. Constipation occurs in up to 39% of patients taking currently available bile acid sequestrants and in severe cases, this may result in fecal impaction. Other gastrointestinal side effects, such as bloating, flatulence, and cramping, also occur in a large percentage of patients who are treated with currently available bile acid sequestrants. Therefore, the development of effective cholesterol-lowering agents with greater tolerability than currently available bile acid sequestrants has been a priority of hypercholesterolemic drug research.
Colesevelam (WelChol/Sankyo) is a new, nonabsorbed polymer (water-absorbing hydrogel) that has been specifically designed to bind to bile acids in the GI tract. It is a poly-allylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and brom hexyltrimethylammonium bromide. Colesevelam has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that colesevelam has superior bile acid binding efficacy compared to cholestyramine. Furthermore, its water-retaining characteristic creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation relative to other bile acid sequestrants.
Pharmacology and Pharmacokinetics
Bile acids are formed from cholesterol in a series of reactions regulated by the enzyme 7-alpha- hydroxylase. During normal digestion, bile acids are secreted into the intestine. A major portion of bile acids are then absorbed from the intestinal tract and returned to the liver via the enterohepatic circulation. Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed (less than 0.05% absorption) from the GI tract. It binds bile acids in the intestine, impeding their reabsorption and facilitating elimination.
As the bile acid pool becomes depleted, the hepatic enzyme cholesterol 7-alpha-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in both increased transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increased numbers of hepatic low-density lipoprotein (LDL) receptors. These compensatory effects result in increased clearance of LDL-C from the blood, thereby decreasing serum LDL-C levels. Furthermore, studies have shown that the combination of colesevelam and an HMG-CoA reductase inhibitor is effective in further lowering serum total-C and LDL-C levels beyond that achieved by either agent alone.
The effectiveness of colesevelam in lowering LDL-C has been demonstrated in a number of controlled clinical trials involving approximately 1,400 patients who were treated for 4–50 weeks. Colesevelam taken alone was found to be effective for patients with mild-to-moderate hypercholesterolemia, producing a maximum therapeutic response within two weeks; this effect was maintained during long-term therapy. In a study in patients with LDL-C between 130 and 220 mg/dL (mean 158 mg/dL), colesevelam was given for 24 weeks in divided doses with the morning and evening meals. In this study, the mean LDL-C reductions were 15% with a 3.8 g dose of colesevelam and 18% with a 4.5 g dose. The mean total-C reductions were 7% and 10%, respectively, and the mean Apo B reductions were 12% in both treatment groups. Colesevelam at both doses also resulted in a 3% increase in HDL-C. There were also small increases in triglycerides (TG) at both colesevelam HCl doses but these were not statistically different from placebo.
In a study of nearly 100 patients with LDL-C between 145 and 250 mg/dL (mean 169 mg/dL), 3.8 g of colesevelam was given for six weeks as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the three dosing regimens, respectively. The reductions with these three regimens were not statistically different from one another. Coadministration of colesevelam and an HMG-CoARI (atorvastatin, lovastatin, or simvastatin) produced an additive reduction of LDL-C in several clinical studies.
Colesevelam doses of 2.3 g to 3.8 g resulted in additional 8% to 16% reductions in LDL-C above that seen with the HMG-CoARI alone. It should be noted that the specific effects of colesevelam, either alone or with an HMG-CoA reductase inhibitor, on cardiovascular morbidity and mortality have not been determined at this time.
Based on these studies, colesevelam, administered alone or in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet and exercise for the reduction of elevated LDL-C in patients with primary hypercholesterolemia who are at significant increased risk for atherosclerotic vascular disease. Prior to initiating colesevelam therapy, it is necessary to first exclude secondary causes of hypercholesterolemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease or other drug therapy.
Also, a lipid profile should be obtained to assess total-C, HDL-C, and TG and periodic serum cholesterol levels, determined as outlined in the National Cholesterol Education Program (NCEP) guidelines to confirm a favorable initial and long-term response. Colesevelam should be used with caution in patients with gastrointestinal disorders (e.g., dysphagia, swallowing disorders, severe gastrointestinal motility disorders, or major gastrointestinal tract surgery) since the safety and efficacy of this drug has not been established in such patients.
In clinical trials, all doses of colesevelam were generally well tolerated. Colesevelam is not absorbed in the digestive tract, reducing the potential for systemic adverse side effects. Also, its water-retaining ability creates a soft, gelatinous material that minimizes the potential for gastrointestinal irritation. The most common side effects reported by patients in clinical trials of colesevelam HCl were flatulence (12% for colesevelam vs. 14% for placebo) and constipation (11% for colesevelam vs. 7% for placebo).
The incidence of gastrointestinal side effects was less than that associated with other drugs in its class. Less than 3% of the trial patients discontinued colesevelam therapy as a result of GI tract adverse reactions. There were no clinically significant changes in serum chemistry parameters from baseline to the end of treatment. In general, the change from baseline for indicators of kidney and liver function did not differ among treatment groups, with the exception of a modest, non-dose-related increase in alkaline phosphatase.
No clinically significant changes were noted during clinical trials to date for hematologic parameters, serum levels of vitamins A and E, prothrombin time, partial thromboplastin time, estradiol levels, body weight, pulse, and systolic and diastolic blood pressure.
In clinical studies, coadministration of colesevelam with atorvastatin, lovastatin, or simvastatin did not interfere with the lipid-lowering activity of the HMG-CoA reductase inhibitor. Colesevelam is reported to decrease the Cmax and AUC of sustained-release verapamil (Calan SR) by approximately 31% and 11%, respectively. Since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear. Colesevelam HCl was found to have no significant effect on the bioavailability of digoxin, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. When administering other drugs for which alterations in blood levels could have a clinically significant effect on safety or efficacy, monitoring drug levels or effects should be considered.
Dosage, Administration and Patient Information
Colesevelam is supplied as an off-white tablet containing 625 mg of the active drug. The recommended initial dose of colesevelam monotherapy is three tablets twice daily or six tablets once daily. Colesevelam should always be taken with a liquid and a meal. The dose of colesevelam may be increased to seven tablets, depending upon the desired therapeutic effect. When used with an HMG-CoA reductase inhibitor, the recommended dose of colesevelam is three tablets taken twice daily with meals or six tablets taken once daily.
Colesevelam and the HMG-CoA reductase inhibitor do not need to be administered at the same time. Patients should be instructed to adhere to their National Cholesterol Education Program recommended diet and inform their physicians if they are pregnant, are intending to become pregnant, or are breastfeeding. Colesevelam is contraindicated in individuals with bowel obstruction and in individuals who have shown hypersensitivity to any of the components of the drug product.