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Value, safety of generics questionable with cataract surgery patients

When choosing antibiotics and anti-inflammatories for your perioperative care, consider the potential side effects.

Issue: June 2012

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John A. Hovanesian

Eye care practitioners should prescribe generic agents cautiously, as harmful side effects have been known to occur with these biologically equivalent alternatives, according to some clinicians.

The U.S. Food and Drug Administration approval process for generic medications requires only proof of bioequivalence; clinical studies on these medications are conducted neither on animals nor on humans to demonstrate safety or efficacy. While similar concentrations of active ingredients must be demonstrated, inactive ingredients may vary widely and have unknown, sometimes toxic, effects on the eye, Primary Care Optometry News Editorial Board Member John A. Hovanesian, MD, FACS, told PCON in an interview.

Paul M. Karpecki

Therefore, practitioners who prescribe these medications must provide informed consent on all of their patients’ pre- and postoperative medication options, which may be a daunting task considering all of the changes occurring in ocular surgery, according to PCON Editorial Board member Paul M. Karpecki, OD, FAAO.

“There are so many changes that have occurred recently in terms of medications and protocols that there is a lack of confidence in comanaging,” he said in an interview.

Risks of generics

The cost benefit of using generics is universally known. Unfortunately, the term “generic equivalency” is an oxymoron, according to Dr. Hovanesian, and studies have shown that brands are safer and tend to work better.

For example, among nonsteroidal anti-inflammatory drugs (NSAIDs), corneal melts and surface toxicity are frequently seen with generic ketorolac as opposed to branded Bromday (bromfenac, Ista), Acular (ketorolac tromethamine, Allergan) and Nevanac (nepafenac, Alcon), Dr. Hovanesian said.

Anterior chamber cell and flare post cataract surgery.

Images: Karpecki PM

“But there’s incredible pressure on patients to go generic or even switch a nongeneric medicine to a generic,” he said.

Patients get pressure from pharmacists who may receive incentives or compensation for switching patients to generics and may be under pressure to promote generics from the pharmacy owner, Dr. Hovanesian said. Promoting generics is also an easy way for pharmacists to achieve a much higher profit margin. Moreover, there is pressure from patients’ drug plans, as well, he said.

Dr. Karpecki added, “It’s unfortunate, because people who can afford only generics are usually the people who can least afford to have something go wrong, too.”

Synechiae caused by iritis.

Nuclear sclerotic cataract

Corneal toxicity caused by a medication: medicamentosa.

Iritis with posterior synechiae.

“On top of all of this,” Dr. Hovanesian added, “there seems to be a false perception among patients that eye drops are not real medicine to begin with, and which product they go with ultimately will not have that much of an effect. So why not go cheaper?”

There is also incredible pressure on patients to switch to generics because of the “donut hole” of Medicare Part D — the period of time for each Medicare beneficiary where prescription coverage is theoretically absent — as such that patients will want the cheapest possible option because they will be paying out of pocket, he said.

However, there have been a few changes to Medicare Part D recently that have altered this dynamic.

First, Medicare beneficiaries, in 2011, became eligible to receive a 50% discount at the pharmacy on brand name drugs and only a 7% discount on equivalent generics, Dr. Hovanesian said.

Second, the full Medicare-negotiated price of brand-name products, not the 50% discounted price, was able to be counted toward the patient’s true out-of-pocket expenses. This means that the full, nondiscounted price is counted toward that $2,850 goal that will enable a beneficiary to exit the donut hole.

Whereas, third, only the actual amount paid for generics (93% of full price) is applied toward the deductible, he said.

“From a strictly financial point of view, generics are less expensive, yes, but not necessarily a better value — especially for those stuck in the donut hole,” Dr. Hovanesian said. “Patients in the donut hole may find it more beneficial, or of better worth, to pay an extra $40 for branded medications in order to exit the donut hole quicker.”

Antibiotic regimen

Antibiotics are generally used 1 to 3 days before and 1 week after surgery. After 1 week, the wounds are usually sealed and no longer require antibiotics, according to Dr. Hovanesian.

“It’s also important to note that the trend toward the use of later-generation fluoroquinolones, such as moxifloxacin and gatifloxacin, is reversing,” he said. “Surgeons are now using less expensive, older fluoroquinolones, such as ofloxacin, and other classes that are more effective against methicillin-resistant Staphylococcus aureus, such as polymyxin or trimethoprim, aminoglycosides (gentamicin and tobramycin) and others.”

Dr. Karpecki agreed with Dr. Hovanesian, except on the matter of the later-generation fluoroquinolone, besifloxacin, “which has seen double digit growth across the board.”

“There is also,” Dr. Hovanesian added, “a current trend toward intracameral antibiotics, which may further reduce risk of postoperative endophthalmitis.”

Dr. Karpecki agreed, but felt it was important to note that this trend is largely European, and not yet widely adopted in the U.S. Anti-inflammatory regimen

Steroids work to reduce the conversion of cell membrane phospholipids to arachidonic acid, which is a pro-inflammatory mediator, Dr. Hovanesian said.

“In the past, steroids alone were considered to be all that was necessary to control inflammation,” he said, “but NSAIDs are now considered essential to reduce risk of cystoid macular edema (CME).”

Dr. Karpecki agreed. “I feel it is best to begin the medications ahead of time,” he said. “Research supports a decrease in CME with prophylactic treatment via an NSAID in cataract patients with nonproliferative diabetic retinopathy.”

“Most surgeons use both steroids and NSAIDs together, but NSAIDs alone may replace steroids as comfort grows,” Dr. Hovanesian said.

“They work on different mechanisms of actions,” Dr. Karpecki said. “So I think there’s added benefit. And some of the newer NSAIDs have almost an anesthetic effect followed by an analgesic effect, which creates a great patient response.

“However, if you look at any sort of neurosurgery, steroids play a critical role,” he said. “And even though surgeons are successfully making smaller and smaller incisions, I still think there’s going to be a critical role for immunological suppression at the arachidonic acid level. NSAIDs will continue to be the mainstay. Dosing of steroids may go down, but I don’t see NSAIDs being used alone for some time.”

According to Dr. Hovanesian, steroids can be dosed from once daily, as with Durezol (difluprednate, Alcon), the strongest steroid, to four times daily with more traditional choices such as Pred Forte (prednisolone acetate, Allergan).

Ester-based steroids, such as Lotemax (loteprednol, Bausch + Lomb), are also effective and may have less risk of IOP rise without much compromise in potency, he said.

“Lotemax is now available as an ointment, though ointments are not used after cataract surgery because of the risk of causing an aggressive, early inflammatory reaction known as toxic anterior segment syndrome, which sometimes occurs with hypopyon,” he said.

Dr. Karpecki supports the use of Lotemax ointment. In a trial with 803 patients using Lotemax ointment (Comstock and colleagues), he said there were no cases of toxic anterior segment syndrome.

“I don’t think the research indicates the syndrome occurring,” he said. “I realize that ointments weren’t used in the past, but this one is preservative-free, and that could be one big advantage.”

Dr. Hovanesian usually applies steroids up to 3 days preoperatively, and postoperative durations of treatment can vary anywhere from less than 1 week (if a potent NSAID is used) to about 4 weeks.

As an exception, Dr. Karpecki added, if working with Crystalens (Bausch + Lomb), treatment will actually continue out to 2 months.

NSAIDs, according to Dr. Hovanesian, work to inhibit the cyclo-oxygenase conversion of arachidonic acid to prostaglandins, which, like arachidonic acid, are pro-inflammatory mediators, and reduce CME. CME occurs when fluid and protein deposits collect on or under the macula, causing it to thicken and swell, from a rare event to 1% incidence.

NSAIDs are especially essential in diabetics, patients with epiretinal membranes, inflamed eyes or anyone with increased vascular permeability due to prior inflammation or vascular disease, he said.

They should be applied up to 3 days before surgery and 1 week to 3 months postoperatively, depending on the custom and comfort of the surgeon, he said. – by Daniel R. Morgan