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Prostaglandin Analogs

Latanoprost
Travoprost
Bimatoprost

Latanoprost
It has become clear, now with about seven years of wide-spread clinical use, that Xalatan (Pfizer, formerly Pharmacia) was the most significant medical milestone in glaucoma therapy since the introduction of timolol in 1978. It is the first, and only, prostaglandin to be approved for first-line therapy. The prostaglandins continue to enjoy the distinction of being the systemically safest drugs to treat glaucoma.

Latanoprost’s predominant mechanism of action is the enhancement of uveoscleral aqueous outflow. Approximately 10% of aqueous outflow in humans is via the uveoscleral pathway. It is generally thought that the prostaglandin analogs biochemically (via matrix metalloproteinases) loosen the intercellular spaces within the face of the ciliary body, enabling enhancement of uveoscleral aqueous outflow. This shifts the outflow dynamics in such a way that perhaps 30% exits via the uveoscleral pathway and 70% exits via the trabecular meshwork.

Studies have shown that latanoprost 0.005%, at one drop per day, reduces IOP more than timolol 0.5% bid, with a much better safety profile. About 90% of patients respond to latanoprost therapy, a rate similar to that of all other topical glaucoma medications.

Latanoprost comes in a 2.5ml bottle containing about 90 drops, which provides about six weeks of bilateral therapy. Instruct patients to squeeze the thin-walled bottle gently to avoid spilling the solution. To enhance patient instillation accuracy, Pfizer has developed Xal-Ease, a very patient-friendly eyedrop dispenser that ensures one targeted drop with each squeeze of the trigger.

The average price to the patient is about $50 to $60 per bottle. That translates to about $450 to $500 per year for bilateral therapy, or just over a dollar a day. Latanoprost is additive to all other contemporary glaucoma drugs.

All medicines seem to have an Achilles’ heel, and the prostaglandin class is no exception. Years of clinical experience have shown that while prostaglandins can cause iris darkening, especially in mixed-colored irides, it is considerably less than originally predicted. These changes are largely cosmetic and carry no known pathological implications. The pigmentary changes represent enhanced production of melanin pigment within the stromal melanocytes and not an increase in the number of melanocytes. There is no “leakage” of pigment from the iris into other ocular tissues.

In practice, this color change potential is rarely a concern to patients, as most of them are thrilled at the success and the simplicity of latanoprost therapy. The key is to educate the patient about this potential side effect prior to initiation of therapy. In general, these irreversible yet subtle pigmentation changes begin to occur six to 12 months into therapy. Such iris color changes are observed in less than 5% of our patients, and have never been a problem.

Now that the prostaglandins have been used extensively, their side-effect profiles, while minimal, are beginning to show. Approximately 5% of patients in one study developed uveitis, and approximately 2% of patients developed cystoid macular edema (CME). The associated iritis was generally low grade and did not develop until after two months of therapy. Iritis or CME, on the rare occasions when it occurs, almost always does so in patients with a history of these conditions, and hardly ever in patients without prior disease.

A recent article has reported a few cases of herpes simplex keratitis thought to be causally associated with prostaglandin use.1 It therefore seems prudent to try other therapies for this small subset of patients until this association is more thoroughly investigated. Based on published literature, it seems reasonable to use the prostaglandins with caution in patients who have:

• a history of uveitis or CME
• aphakia
• YAG posterior capsulotomy
• an anterior chamber IOL
• a history of herpes simplex keratitis

Hypertrichosis, a darkening, lengthening, and thickening of eyelashes, seems to be the most common side effect seen with the prostaglandin class. Whether this is a desired or undesired side effect may be in the eye of the glaucoma patient, much like the iris color change. Note however that such an effect could be of cosmetic concern in some patients, so discuss this possibility in unilateral therapy.

Lastly, be aware that vague flu-like symptoms
can be caused by prostaglandin drugs. Such an occurrence is rare, but the astute clinician is always cognizant and vigilant.

It generally takes about two weeks for the prostaglandins to achieve maximum, or near-maximum, therapeutic effect. For this reason, start the patient on a monocular therapeutic trial and reevaluate the patient in two to three weeks. Once a therapeutic benefit has been established, continue with bilateral therapy, if indicated.

In summary, while all the prostaglandins have equivalent IOP-reducing ability, Xalatan is the best tolerated (regarding side effects) of the class, and therefore is the most clinically useful. It is our most often prescribed chronic-care drug.

Travoprost
Of the prostaglandins, travoprost most closely mimics all the characteristics of latanoprost. We like the clear bottles of Xalatan and Travatan (Alcon) so patients can monitor their supply. However, it is important to preemptively explain to patients that both are purposefully half-filled to facilitate “dropper-ability.” This will curb some whining about, “This little bottle is only half-full!”

Travoprost is a similar drug to latanoprost, and appears to have a similar performance and side effect profile. Travoprost is available in a 2.5 ml and a 5 ml clear bottle.



Bimatoprost
Lumigan (Allergan) is the third member of this elite drug class. Because of its somewhat unique chemical structure, it has to be more concentrated, i.e., 0.03% (versus 0.005% latanoprost and 0.004% travoprost).

Lumigan reduces IOP very similarly to Xalatan and Travatan—about 30%. It is to be used once daily, like Xalatan and Travatan.

Lumigan is a potent prostaglandin drug that, when used once daily, can reduce IOP about 30% with minimal side effect potential. It does have the greatest tendency of the three to cause conjunctival hyperemia. Patients should be advised of this possibility up front to avoid unnecessary call-backs.

Since compliance is largely influenced by tolerability, we constantly strive to prescribe medicines that are most likely to be used consistently without the physical and psychological deterrent of side effects.

Lumigan is the only prostaglandin to come in an opaque bottle. This has the advantage of preventing patients from complaining about the bottle being only half-full; however, the disadvantage is that patients cannot judge when the bottle is nearly empty, and some patients who fail to plan ahead may occasionally miss dosing.

Lumigan is available in 2.5ml, 5.0ml, and 7.5ml quantities, which are all packaged in 8ml-size bottles. There are some insurance plans that cover medicines for up to a three-month supply with only one co-pay. Having 7.5ml of solution available in one bottle could prove very cost-saving for patients with such plans. It is important to have some knowledge of prescription benefit co-pays, because some insurance policies consider a “month’s supply” of a prostaglandin to be 2.5ml. Otherwise, an out-of-pocket charge of $140 for a 7.5ml bottle could create serious sticker-shock at the pharmacy check-out counter.