Considerations for Fixed-Dose Combination Products in Cardiometabolic Disease

As more fixed-dose combination products receive approval, pharmacists should familiarize themselves with these drugs' advantages and disadvantages.

Over the years, the landscape of combination products for cardiometabolic conditions has evolved considerably. Starting in the 1960s, combination product containing thiazide diuretics, such as Dyazide (triamterene and hydrochlorothiazide) and Ser-Ap-Es (hydralazine, hydrochlorothiazide, and reserpine), became available for the treatment of hypertension. In the ’70’s and ’80s, combinations with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers came into play. ¹ In the early 2000s, the range of combination treatments extended to the management of type 2 diabetes mellitus (T2DM) and dyslipidemias with products such as Glucovance (glyburide and metformin) and Advicor (niacin extended-release and lovastatin), respectively. ²

With the knowledge that multiple clinical factors can impact cardiovascular risk, the concept of parallel management of multiple disorders helped define the need for products capable of multitasking. Thus, a combination of the antihypertensive amlodipine and lipid-lowering agent atorvastatin (Caduet) came onto the market in 2004. Most recently, in October 2011, the FDA approved Juvisync, a fixed-dose combination of sitagliptin and simvastatin that is the first product approved to improve glycemic control and lower cholesterol.

A list of recently approved combination products is presented in the Table, which represents only a fraction of the products available. Due to the potential value to patients and clinicians and the profitability of these products to manufacturers, the development of new and novel drug combinations is sure to continue. Pharmacists should be aware of the role of these products, including their advantages and disadvantages, to enable them to effectively counsel patients and advise physicians about their use.

The Pros

Perhaps the most obvious advantage to drug combinations is the potential improvement in patient compliance. Attempting to quantify this improvement, researchers conducted a meta-analysis that included, among others, patients with hypertension and diabetes. Patients took either fixeddose combinations or “free-drug” components of the therapeutic regimen given separately. The fixed-dose combination group demonstrated a 26% relative risk (RR) reduction of noncompliance (RR 0.74; 95% confidence interval, 0.69-0.80). ³

In another analysis of patients with T2DM taking fixed-dose drug combinations or a combination of single pills, patients taking the fixed-dose drug combinations had improved satisfaction and lower direct medical costs, in addition to improved compliance. ⁴

However, these data support the conclusion that combinations can improve effectiveness, not efficacy. ⁵ Efficacy is a measure of a drug’s performance in a controlled setting, like a clinical trial, whereas effectiveness is a measure of performance in real practice, where compliance is not as strictly enforced. ⁶ The distinction is important because not all combinations are more efficacious than their separate components, but they may be more effective, because data have shown that patients are more compliant if their regimens are less complex. ⁵

Drug combinations can confer other advantages besides patient compliance. According to the Seventh Report of the Joint National Committee, patients taking antihypertensive combinations may also have fewer side effects, because the doses of the agents in the combination product may be less than if they were prescribed separately. ⁷ This may be due to the fact that most antihypertensives exhibit most of their blood pressure—lowering effects at lower dose ranges, with smaller reductions as the dose is increased. This is why adding additional agents at a low dose is better than increasing the dose of just a single agent. ¹ Finally, some patients may save money with combination products because they will have fewer copays, thus improving access to therapy.

The Cons

Combination products are not without some disadvantages. One of these is cost, specifically with branded combinations. In a study that compared the cost of commonly prescribed brand-name combinations for the treatment of hypertension with their generic components, researchers found that the brand-name group had higher out-of-pocket costs, but lower total costs. ⁸ The authors concluded, “Given patient burden and nonadherence from out-of-pocket prescription costs, the clinical benefits of brand-named fixed-dose combination antihypertensive therapy should be balanced with their greater outof-pocket costs.” ⁸ In short, combination products may not always be appropriate for patients; costs may be similar for patients who are already taking 1 or more branded agents, but more costly if they are currently using multiple generics.

The other obvious disadvantage to combination products is that they are “fixed” doses and are not available in every possible dosing combination of their component drugs. Therefore, physicians do lose some level of flexibility when a combination product is desired, but a patient requires an unavailable dosage.

One last point to keep in mind is that although patients on antihypertensive combinations may experience fewer side effects, combinations make it more difficult to determine the offending agent if the patient experiences an adverse event. ¹ Because some combinations are approved for initial therapy, this could become problematic for adverse events not commonly associated with certain drug classes, rare events, or hypersensitivity reactions.

Looking Ahead

For diseases for which therapies are becoming increasingly more targeted, we can expect more drugs that are “codeveloped,” allowing companies to test drugs in combinations that have not been previously marketed. ^9,10 Because most combinations consist of drugs that have already been formulated separately, codeveloped products will usher in a new age of combination therapy.

Researchers are also investigating the use of treatments that have a greater number of active ingredients. In a recently published international study, the use of a combination pill containing aspirin, lisinopril, hydrochlorothiazide, and simvastatin was shown to halve the risk of heart disease and stroke risk compared with controls. ¹¹ Although this type of product may not be commercially available anytime soon, the principle is promising for patients with high risk of cardiovascular events based on multiple risk factors.

The Role of The Pharmacist

With the growing availability of combination products and their increasing complexity, counseling patients on compliance will be even more important. Although taking a single pill will be more convenient for the patient, pharmacists must be aware that it is also a doubleedged sword. With combination products, a noncompliant patient may be forgetting to treat not just 1 serious condition, but 2. If patients are taking branded products, they should be made explicitly aware of the agents in the combination so they do not think they are receiving only 1 active ingredient. Because cost may be an issue, pharmacists should keep up-to-date with generic availabilities of combination products and their components so that they can make appropriate recommendations to physicians. As members of the health care team, pharmacists can help ensure the judicious use of these products for the benefit and safety of their patients. PT

Dr. Prescott is vice president, clinical and scientific affairs, for Pharmacy Times. Mr. Manalo is a PharmD candidate at the Ernest Mario School of Pharmacy at Rutgers University in Piscataway, New Jersey.

References

1. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs. 2002;62(3):443-462.

2. Leichter SB, Thomas S. Combination medications in diabetes care: an opportunity that merits more attention. Clin Diabetes. 2003;21(4):175-178.

3. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-719.

4. Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of compliance, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011;27(6):1157-1168.

5. Podolsky SH, Greene JA. Combination drugs—hype, harm, and hope. N Engl J Med. 2011;356(6):488-491.

6. Glasgow RE, Lichtenstein E, Marcus AC. Why don’t we see more translation of health promotion research to practice? rethinking the efficacy-to-effectiveness transition. Am J Public Health. 2003;93(8):1261-1267.

7. National Institutes of Health National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2004:1-86.

8. Rabbani A, Alexander GC. Out-of-pocket and total costs of fixed-dose combination antihypertensives and their components. Am J Hypertens. 2008;21(5):509-513.

9. Woodcock J, Griffin JP, Behrman RE. Development of novel combination therapies. N Engl J Med. 2011;364(11):985-987.

10. Food and Drug Administration. Guidance for Industry — Codevelopment of Two or More Unmarketed Investigational Drugs For Use in Combination. FDA Web site. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM236669.pdf. 2010:1-9.

11. PILL Collaborative Group; Rodgers A, Patel, A, Berwanger O, et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PLoS One. 2011;6(5):e19857.

12. Drugs@FDA resources page. Food and Drug Administration Web site. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Updated daily. Accessed October 31, 2011.