Combination Therapy
Chat Highlights
March 1, 2006

On Wednesday, March 1, 2006, Dr. Elliot Werner, a glaucoma specialist at Wills, and the glaucoma chat group discussed "Combination Therapy."

Moderator:  Welcome, Dr. Werner.  The topic tonight is "Combination Therapy."  Will you please begin by explaining what that means?

Dr. Elliot Werner:  Combination therapy refers to the use of more than one drug to treat a particular condition, because the combination works better than any of the drugs used individually.

Moderator:   What's the difference between free-combination therapy and fixed-combination therapy?

Dr. Elliot Werner:   Free-combination therapy refers to the use of the drugs in a way that the dosage of each one can be varied independently of the other drugs.  Fixed combination refers to the use of the drugs in fixed or standard dosages.  If you want to vary the dose in a fixed combination treatment, you have to vary the dose of all the agents at the same time.

Moderator:   How many drugs are combined in fixed-combination treatment?

Dr. Elliot Werner:   Most-fixed combination therapies have two or more drugs combined in a single pill or drop.

P:  What are some of the fixed-combination drugs?

Dr. Elliot Werner:   In glaucoma, the most commonly used fixed-combination agent is Cosopt, which is a fixed combination of Trusopt and timolol.  There are some older combinations, such as E-pilo, which is a fixed combination of epinephrine and pilocarpine, but it is rarely used anymore.  In Europe, there is Xalcom, which is a fixed combination of Xalatan and timolol, but it is not available in the USA. I think it is also available in Canada.

P:   What are the different classes of glaucoma drugs and how do they differ?

Dr. Elliot Werner:   There are two classes of drugs, miotics (pilocarpine, carbachol) and prostaglandins (Xalatan, Travatan, Lumigan) that lower intraocular pressure by increasing outflow; that is, they move the fluid out of the eye faster.  The beta blockers (timolol, Betagan, Betoptic), adrenergics (epinephrine, Alphagan, brimonidine), and carbonic anhydrase inhibitors (Diamox, Trusopt, Azopt, Neptazane) lower intraocular pressure (IOP) by decreasing aqueous humor secretion.

P:   When starting combination therapy, is the idea to add a drop that has a different but complementary function?

Dr. Elliot Werner:   The ideal combination therapies combine two or more agents that are additive, or more than additive, in their effects.  Some combinations are less than additive, such as combining prostaglandins and miotics.

P:   Do some fixed combinations use eyedrops from different drug companies?

Dr. Elliot Werner:   The only fixed combination I am really familiar with in the USA is Cosopt, and both agents are made by Merck.  In some cases, such as Xalcom, Xalatan is made by Pfizer and timolol is generically available, so it can be made by anybody.  Competing drug companies rarely cooperate to produce a fixed-combination product, unless one company buys a license from the other.

P:   If one drop is not doing the job, would you switch the patient's medication to a fixed combination drop right away, or add the second drop to see if it helps, and then switch to the fixed combination?  If the two don't work as a free combination, are they likely to work in fixed combination?

Dr. Elliot Werner:   It depends on to what extent the first drop "is not working".  If it doesn't work at all, that is, the pressure is the same after the drug as before, there is no point in continuing the agent.  It should be stopped and a new drug tried.  If it works a little, but not as well as desired -- that is, it lowers the pressure but not as much as you would like -- then a combination makes sense by adding another drop.  If two agents do not work together as a free combination, they will not work together as a fixed combination either.

P:   Is there a consensus about whether free- or fixed-combination therapy is more effective?

Dr. Elliot Werner:   In order to get FDA approval, a fixed combination must be at least as effective as the two agents given in a free combination.  Generally, they are equally effective, so long as the chemistry of the two drugs allows mixing them together in one pill or bottle.  The major advantage of fixed combinations is convenience for the patient.

P:   If you add a medication, are you also adding side effects? Is there an advantage to fixed combinations in terms of side effects?

Dr. Elliot Werner:   Probably not.  The side effect-profile of fixed and free combinations will be about the same.  The major advantage of free combinations is that if you have side effects to one agent, you can adjust its dose without changing the other.

P:   If a drop is no longer effective and another drop is added, should the original drop be stopped or is that risky?

Dr. Elliot Werner:   If the drug is no longer effective, it's probably better to stop and switch.  If it is still having some effect but not enough, then you add another drop.  The real purpose of combination therapy is to use it to treat a condition because it is shown to be more effective than any single therapy.  That is not really the case in glaucoma.

P:   Would you please explain?

Dr. Elliot Werner:   The point of combination therapy is that it has been shown to be far more effective than single therapy for a particular condition, so it is used routinely in that condition.  That is not the case for glaucoma, so the use of the term "combination therapy" is a little misleading.

P:   Since Cosopt [dorzolamide hydrochloride-timolol maleate] is a combination, would it be a second choice after trying the drugs separately?

Dr. Elliot Werner:   For glaucoma, yes, because there is no evidence that using Cosopt as a primary treatment is better than a single drug that lowers the IOP adequately.  That is different from tuberculosis, for example, where initial treatment with combination therapy is far more effective than any agent alone.

P:   Aren't there fewer preservatives in fixed-combination products?

Dr. Elliot Werner:   That is correct, and another potential advantage of combination products.  The biggest obstacle to developing combination products for glaucoma has been chemical interactions of the drugs when in solution in the same bottle, which tends to reduce their effectiveness.

P:   Do you think beta blockers should be avoided in pigmentary glaucoma since, with less aqueous, the density of free pigment will become greater?  If so, what could be added to a prostaglandin analog in a patient with pigmentary glaucoma?

Dr. Elliot Werner:   I think that is a theoretical objection, but has not been shown.  Both beta blockers and prostaglandins can be very safe and effective in pigmentary glaucoma.

Moderator:   Dr. Werner, before you leave, do you have any further comments about combination therapy?

Dr. Elliot Werner:   Combination therapy, as distinct from monotherapy, is really more important in treating disease other than glaucoma.  For example, it has been shown that combination therapy is much more effective in treating tuberculosis, AIDS, or severe hypertension -- to name a few --than is single therapy. Therefore, initial treatment of those diseases usually involves combination therapy from the start.

Glaucoma is usually not treated with combination therapy as a first-line treatment.  We start with one drug. If that is inadequate, we add another. But unlike some other conditions, combination therapies are not standard treatment in glaucoma.

Moderator:   Thank you so much for your time and great responses.

Dr. Elliot Werner:   You're welcome.  I'll see you all next time.

On March 8, Dr. Wilson discussed "Common Mistakes Patients Make" in the Chat room. Click here for highlights of that meeting.

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