Combinations can provide two drugs in one pill

The Baltimore Sun

The Rev. Eddie Martin was willing to take two drugs, a diuretic and a calcium channel blocker, to get his blood pressure down. But when his doctor decided to add a third pill, a cholesterol-lowering medication, to Martin's daily medicine regimen, the reverend balked.

"I just hate taking pills," Martin says, "and what's more, with each extra drug, that's another co-pay I've got to shell out."

Then the Woodland, Ohio, resident heard a TV ad for Caduet, which combines the blood-pressure-lowering drug Norvasc with the cholesterol-reducing medicine Lipitor. Martin's doctor agreed that Caduet could take care of his patient's blood pressure and cholesterol-lowering needs and prescribed the drug, leaving the reverend's drug count at a total of two per day.

"Now, I'm getting the drugs I need without extra pills or extra cost," Martin says.

Although pharmacy cough and cold sections have long been filled with remedies that combine four and even five ingredients to stop sniffles, fever, congestion and headache in a single dose, prescription drugs are increasingly offered as combination therapies as well.

Pills that include two cholesterol-lowering drugs are the fastest-growing segment of the cholesterol-lowering market, health business analysts say.

The Food and Drug Administration recently approved a medication, Atripla, that combines three drugs to treat HIV. Although physicians treating medical conditions such as diabetes or high blood pressure often start patients on a single drug until they can see how well it works and what the side effects are, that could begin to change.

In April, the Food and Drug Administration held a hearing to consider approving Bristol-Myers Squibb and Sanofi-Synthelabo's drug Avalide, a combination of two already-available blood-pressure lowering drugs, for first-line therapy. That's the initial treatment recommended for a disease or condition.

"Combination drugs are likely to benefit a great many people who are already taking the same drugs separately," says Richard Fisler, president of Beachhead Consulting, who has published a market research report on combination therapies.

That doesn't mean the drugs are the best choice for everyone. If a patient is already taking Norvasc and Lipitor - and having two insurance copays - taking the drugs as a single Caduet pill will reduce the number of pills he or she has to take, and, for many people, will bring the two copays down to one, Fisler says.

But while Caduet comes in 11 dosing regimens, other combinations may come only as one or two, preventing a physician from finding the optimum dose of each drug.

And the new combination drugs can sometimes end up costing more than separate generics, depending on a person's insurance coverage.

Bonus for companies

Several factors are behind the recent push to introduce new combination products.

Companies facing patent expirations and lowered revenues from generic competition can reap at least some of the cash back by patenting a combination drug. For example, the patent for Norvasc, one of the two drugs in Caduet, expires this year, and the patent for the other drug, Lipitor, expires in 2010.

Pfizer, which makes Norvasc and Lipitor, has already seen annual sales of Lipitor drop by billions because of competition from generic versions of Merck's cholesterol medication Zocor, which lost its patent this year. Annual sales for Norvasc, approved in 1992, are $5 billion.

But while a manufacturer's main motive may be profit, physicians hope that the combination drugs can improve patient compliance with their medications. According to a 2004 presentation at the Annual Scientific Session of the American College of Cardiology, more than half of patients with heart disease failed to strictly adhere to their drug regimen to lower blood pressure and cholesterol.

Financially, the patient can often come out ahead with a combination drug, but not always, says Dr. William Shrank, a pharmacoepidemiologist at the Harvard Medical School.

Fisler's report on combination drugs compared combination and single drug prices at 30 retail pharmacies and two online pharmacies and found that some combos saved patients money, while some did not.

He found that patients taking such combinations as Caduet and Vytorin (which combines the drugs Zetia and Zocor, both of which lower cholesterol but in different ways) saved $15 to $103 per month.

And, an online pharmacy, lists a one-month supply of the blood-pressure-lowering drug Avalide (150 milligrams of Avapro, 12.5 milligrams of hydrochlorathiazide) at $59.99. The cost of buying the component drugs separately for a one-month supply is $66.99, or $84 more per year.

But combinations don't always bear out a financial advantage. lists $74.40 for a one-month supply of the combination blood pressure-lowering drug Lotrel, which contains amlodipine (Norvasc) and benazepril (Lotensin) at the dosage strength of 2.5 milligrams of amlodipene and 10 milligrams of benazepril.

Buying a 30-day supply of each drug separately at the same dosage strengths would cost patients $66.99.

Insured patients are more likely to save money, but only if the insurer actually covers the combination drug. Some don't cover the cost of Caduet, so patients who want it have to pay the retail price of about $150 for a 30-day supply of the drug. Its two components, Norvasc and Lipitor, usually cost $40 to $70 per month in copays.


Convenience and cost aside, some drugs are clinically better as a combination. A good example is Augmentin, an antibiotic that combines the generic drug amoxicillin with clavulanic acid, which prevents the amoxicillin from being broken down by enzymes in the body.

Dr. Daniel Berger, an endocrinologist in private practice in Santa Barbara, Calif., says physicians may ultimately find a synergistic effect of other combinations as well, say, for pain or diabetes. Such dual action may let doctors prescribe lower doses of each drug in combination than they could as separate medicines, increasing the benefit and reducing side effects.

Metformin, for example, one of two drugs in the combination diabetes medicine Janumet, causes gastrointestinal side effects, while Januvia, the second drug in the combo, does not. If a combo allows a doctor to lower a patient's metformin dose, he or she may get good diabetes control and reduced side effects.

At least one company, CombinatoRx of Cambridge, Mass., is working specifically on synergistic combinations. Though most combination drugs are already used together, the firm is investigating drugs from different treatment areas. For example, the antidepressant amoxapine could be combined with dipyridamole, a drug that prevents blood clots after heart-valve replacement. The company thinks the combination can treat inflammatory diseases such as arthritis, although neither is used that way now.

Although the triple HIV drug Atripla is the most ambitious combination on the market, a 600-patient clinical trial of a four-drug "super-pill" aimed at preventing heart disease will begin this year in New Zealand, India, Australia, Brazil, China, South Africa and Britain.

The pill would contain aspirin, a cholesterol-lowering drug and two blood pressure drugs. Combination drugs are likely to benefit a great many people who are already taking the same drugs separately, proponents say.

Francesca Lunzer Kritz wrote this article for the Los Angeles Times.

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