Drug shortages put ophthalmologists and their patients in difficult positions

Confirmed drug shortages can limit a patient’s access to needed medications and force ophthalmologists to make difficult decisions regarding patient care.

Historically, drugs in short supply have been low-profit margin generic medicines, which can be challenging to manufacture, former FDA Commissioner Scott Gottlieb, MD, said in a July 2018 statement.

The sterile, parenteral drugs have low-profit margins, so the only way to produce them is to manufacture them at a “tremendous scale,” he said.

Source: Nathan M. Radcliffe, MD

“This has resulted in fewer and fewer manufacturers for certain key products. The result is very little margin for error in this space,” Gottlieb said in the statement.

Current ophthalmic shortages

As of June 6, 2019, the FDA listed 15 separate ophthalmic drugs currently in a shortage or discontinued from use.

Dorzolamide hydrochloride ophthalmic solution and dorzolamide hydrochloride-timolol maleate ophthalmic solution, two glaucoma medications, are both listed as currently in shortages by the FDA and have experienced several shortages since fall 2017, Nathan M. Radcliffe, MD, a clinical associate professor of ophthalmology at New York Eye and Ear Infirmary and a cataract and glaucoma surgeon at New York Eye Surgery Center, said.

At the time of the first shortage, Radcliffe said there were roughly six classes of medications to treat glaucoma; prostaglandin analogues, beta-blockers, alpha-2 agonists, carbonic anhydrase inhibitors, miotics and the new Rho kinase inhibitors. Dorzolamide and dorzolamide-timolol were in the carbonic anhydrase inhibitor class, mostly available in generic forms, and more affordable compared with Azopt (brinzolamide ophthalmic suspension, Alcon), a branded glaucoma medication.

“You couldn’t simply swap a patient on dorzolamide to the other medications in those classes because you’d run into coverage problems, very high copays or other problems,” Radcliffe said.

Radcliffe said dorzolamide shortages hit suddenly and left many patients without the ability to fill their glaucoma medication prescriptions. Many were turned away by their pharmacies because they simply did not have the medication available, and many patients did not contact his office to find another solution.

While dorzolamide did fail to outperform placebo in the European Glaucoma Prevention Study, patients on the fixed combination of dorzolamide and timolol experienced much more disruption in their treatments during the shortages, he said.

“It’s a reasonably effective drug. It’s not the best out there, but it is reasonable. We should have access to it, but for whatever reason in the current pharmaceutical environment, with respect to generic manufacturing, we cannot create a situation where the drug is in consistent supply. I don’t prescribe it anymore unless absolutely forced to. I always try to avoid it because I worry that setting a patient up with a dorzolamide-containing prescription may give them a bottle today but a nightmare tomorrow,” he said. “I have seen a number of patients experience severe vision loss after losing a dorzolamide-containing script when the shortage hit.”

Avoiding drug shortages

Limiting the drug’s use is the best short-term solution. However, devising a long-term solution may be difficult because the reason for the shortage is vague, Radcliffe said.

The FDA lists the reason for the dorzolamide shortage as “manufacturing issues” on its official shortage list. According to a 2018 statement from Gottlieb, most drug shortages are due to manufacturing and quality issues, such as outdated equipment in need of repair or replacement, unexpected issues regarding a drug’s composition, or a manufacturer’s inability to maintain product and facility quality.

The FDA continually monitors potential and ongoing shortages. The FDA’s Drug Shortages Staff receives reports from sources related to drug shortages and discontinuations and will verify them through communications with manufacturers, other FDA offices and external entities, Wiley Chambers, MD, an ophthalmologist with the FDA Office of New Drugs, said.

In 2017, the FDA reported 35 drug shortages and 132 averted drug shortages. As shortages arise, the FDA takes “immediate action” within its authorities to minimize the impact and maintain or restore availability of critical medicines for patients who need them, he said.

“The FDA will identify, review related information and monitor the supply of products from alternate sources related to drug shortages when necessary. With early communication with manufacturers and various Center for Drug Evaluation and Research offices, the FDA can work with the various stakeholders to avert shortages if possible,” Chambers said.

Drug prices during shortages

Shortages have a definitive effect on drug prices. According to findings published in Annals of Internal Medicine, drug prices increase two times as quickly as they would have in the absence of a shortage.

Inmaculada Hernandez, PharmD, PhD, from the University of Pittsburgh School of Pharmacy, and colleagues evaluated the relationship between price changes and drug shortages. The researchers identified 917 drugs with active shortages between December 2015 and December 2016 and obtained their generic names, National Drug Code (NDC) numbers and shortage start dates. Researchers obtained wholesale acquisition costs for each NDC number for the first month of shortage and the next 12 months.

The final sample included 617 NDC numbers for 90 drug products. Data indicated a 7.3% increase in the prices of all drugs in the 11 months before the shortage began and a 16% increase in the 11 months after.

The FDA does not play a direct role in drug pricing; it is the responsibility of manufacturers, distributors and retailers, among others, to establish prices, Chambers said.

However, too many patients are still being priced out of medicines they need, he noted.

“No patient should be priced out of the medicines they need, and as an agency dedicated to promoting public health, we must do our part to help patients get access to the treatments they require,” he said.

Yet shortages persist and can be attributed to any number of factors, Michael X. Repka, MD, MBA, American Academy of Ophthalmology medical director for governmental affairs, said.

Shortages in the generic space

Shortages can be caused by manufacturers in the generic space stopping production of a drug because their profit margins are too low. When prices get too low, the manufacturers may stop production if they can no longer make a profit with a generic drug.

“There’s no compulsion for them to make the product. You can say that every drug company’s mission is to advance the public health, but if their margins are insufficient, it’s a wonderful sentiment but it’s hard for a manufacturer to do,” Repka said.

Market forces and extreme competition in the generic marketplace can drive prices down, which is good for patients, but may be counterproductive in terms of a constant drug supply. If the market continually drops and several manufacturers are forced to pull out of the space, the remaining manufacturers may not have the capacity or the funding to increase production to accommodate the need for a drug, he said.

“Whether or not they can get the financing to ramp up, that’s the real problem,” he said.

Additionally, ophthalmologists should be wary about a drug that is being actively manufactured by only one or two companies. Dorzolamide-timolol had eight manufacturers, of which only two were actively making the product before its shortage, Repka said.

Generics can be cost-effective

When the generic market is working and balanced, it is a great option for ophthalmologists and patients to keep treatment costs down and explore other avenues of treatment, OSN Cornea/External Disease Board Member Darrell E. White, MD, said.

Latanoprost, for example, is equal to its branded counterpart, Xalatan (latanoprost 0.005%, Pfizer), is manufactured by 10 to 12 different companies and is less expensive, he said.

“You have a medication which is precisely the equivalent to the brand, and you have lots of different competing manufacturers, so there’s a true price-based marketplace. That’s what’s supposed to happen,” White said.

But when a price-based marketplace does not exist, generics can often be as expensive as their branded counterparts. For example, Pred Forte (prednisolone acetate, Allergan) and other prednisolone suspensions have had their marketplaces disrupted by shortages, White said.

Generic manufacturers were able to fill the void during the prednisolone acetate shortage, but they had little marketplace competition and prices for the generic drugs rose, White said.

“Currently, there is only a very small cost difference between branded and generic topical prednisolone medications. There is no classic generic market there, in the sense that there is no generic pressure on pricing, whereas with timolol or latanoprost, you have generic brand equivalents at lower prices. You’ve got many players in the marketplace, and it’s a classic supply-and-demand setup, with lots of price competition,” he said.

Not always less expensive

The cost of a generic form of a drug is not always less expensive than the brand-name medication. With manufacturer coupons or discount cards, branded medications can rival the cost of many generics, Healio.com/OSN Section Editor Uday Devgan, MD, said.

“In my private practice, I do not typically use generic drugs for cataract surgery patients. I find that I am able to use the brand-name drugs, which offer better dosing and more potency while still being covered by most insurance plans. At our county hospital where I teach residents in training, the hospital formulary is more restrictive and we use primarily generic drugs,” he said.

Cost of medication, especially in the cataract surgery space, is an important issue. In rare cases, the cost of eye drops can match or exceed the surgeon fee for cataract surgery itself. Ideally, surgeons and patients would have access to low-cost medications that were convenient and efficacious, he said.

Surgeons should provide the best drug options for their patients within their budget or insurance plan. Finding options to keep costs down should be explored, Devgan said.

“There are also compounding pharmacies which can provide us with medications, often in mixtures which are not otherwise available. There are antibiotic, steroid, NSAID topical combinations which can prove to be cost-effective. We can also use injectable medications into the anterior chamber, the vitreous cavity or subconjunctival/sub-Tenon’s space. Finally, there are new depot formulations of steroids that can be placed behind the iris or even intracanalicularly,” he said.

Alternate routes for drug acquisition

Exploring different routes of acquiring drugs, such as a compounding pharmacy or a specialty pharmacy, can be an effective solution during shortages, White said. However, ophthalmologists should be careful when using a compounding pharmacy.

“Some compounding pharmacies have exploited the fact that combination medicines don’t exist in many of these spaces. They create combination medicines that allow patients to take their desired combination from one bottle. That is their entry point into this marketplace, but some have been very aggressive at compounding very slightly altered versions of an FDA approved product. ... There’s less oversight of that entire market,” he said.

The best option to acquire hard-to-find drugs may be specialty pharmacies. Eagle Pharmacy, for example, is often the only option to obtain generic AzaSite (azithromycin ophthalmic solution, Akorn), a topical azithromycin delivery in a DuraSite vehicle for the treatment of bacterial conjunctivitis.

Azithromycin ophthalmic solution, used in the dry eye community for the treatment of meibomian gland disease and evaporative dry eye, is an effective drug but has been in a shortage for the past several years, White said.

“Eagle Pharmacy is often the only option I have to obtain AzaSite or a non-preserved Cosopt (dorzolamide hydrochloride, timolol maleate, Akorn). In some cases, it’s the only way you can source those. As a doctor, you need to be willing to learn these alternate avenues exist and learn how to function in that environment,” he said.

Look for cheaper alternatives

Shortages are always a concern, but drug pricing may be the bigger long-term issue, OSN Pediatrics/Strabismus Section Editor Robert S. Gold, MD, said.

In the pediatric ophthalmic space, even if patients have insurance, brand-name medications can “cost an astronomical amount of money.” Neo-Poly-Dex, the generic version of Maxitrol (neomycin, polymyxin B sulfate, dexamethasone ophthalmic suspension, Alcon), a commonly used antibiotic and steroid medicine used to treat eye infection and inflammation, is typically about $10 per bottle or even less when covered by a patient’s insurance and much less expensive compared with the branded drug.

“If you prescribe a medication without cost in mind, you’re most likely going to get a call from the patient or pharmacy that says the family can’t afford the drug or isn’t willing to afford it. In our practice, we prescribe medicines that we feel are affordable. We go over the side effects with the patients and the family, and we let them know that if there is a problem, they need to let us know,” Gold said.

Even with antibiotic drops, first- and second-generation generics cost much less than recently branded medications. Ophthalmologists need to educate themselves about what drugs are covered under their patients’ plans and what can be substituted in case a branded drug is too expensive, Gold said.

Sometimes there is no solution

But at times shortages are inevitable, and costlier drugs may be the only option. When prednisolone acetate 1% was experiencing a shortage, the best substitute was the stronger branded drug Durezol (difluprednate ophthalmic emulsion 0.05%, Novartis). While the drug is more potent than prednisolone acetate 1%, it is also more expensive, Gold said.

“While there are shortages, they’re usually short-lived. When there are drug shortages there are alternatives, but the alternatives usually come with a cost. I try to be cost-effective for my patients until such time that I can’t,” Gold said.

Limiting drug shortages, identifying the root causes of shortages and minimizing the impact of shortages when they occur will continue to be points of emphasis for the FDA. The FDA has taken steps under its Drug Competition Action Plan and Biosimilar Action Plan to promote policies to broaden access to safe and effective generic and biosimilar drugs, Chambers said.

“Getting safe and effective generic products to market in an efficient way, being risk-based in our own work and making sure our rules aren’t used to create obstacles to new competition can all help make sure that patients have access to more lower-cost options,” he said. – by Robert Linnehan

• References:
• Current and resolved drug shortages and discontinuations reported to FDA. www.accessdata.fda.gov/scripts/drugshortages/default.cfm. Accessed July 2, 2018.
• Drug shortages infographic. www.fda.gov/drugs/drug-shortages/text-version-drug-shortages-infographic. Accessed July 2, 2019.
• Forand R. Encouraging competition ‘key’ to reducing glaucoma medication prices. https://www.healio.com/news/ophthalmology/20181027/encouraging-competition-key-to-reducing-glaucoma-medication-prices. Published Oct. 27, 2018. Accessed July 1, 2019.
• Miglior S, et al. Ophthalmology. 2005;doi:10.1016/j.ophtha.2004.11.030.
• Statement from FDA Commissioner Scott Gottlieb, MD, on FDA’s work to mitigate shortages of intravenous drugs, shorten supply disruptions and better predict vulnerabilities. www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-fdas-work-mitigate-shortages-intravenous-drugs-shorten. Published May 31, 2018. Accessed July 2, 2019.
• Statement by FDA Commissioner Scott Gottlieb, MD, on formation of a new drug shortages task force and FDA’s efforts to advance long-term solutions to prevent shortages. www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-formation-new-drug-shortages-task-force-and-fdas. Published July 12, 2018. Accessed July 1, 2019.
• Tedesco A. Drug prices rise twice as fast during shortages. https://www.healio.com/news/primary-care/20180917/drug-prices-rise-twice-as-fast-during-shortages. Published Sept. 17, 2018. Accessed July 1, 2019.

• For more information:
• Wiley Chambers, MD, can be reached at Food and Drug Administration, Center for Drug Evaluation and Research, Office of Antimicrobial Products, 10903 New Hampshire Ave., Silver Spring, MD 20993; email: wiley.chambers@fda.hhs.gov.
• Uday Devgan, MD, can be reached at Devgan Eye Surgery, 11600 Wilshire Blvd. #200, Los Angeles, CA 90025; email: devgan@gmail.com.
• Robert S. Gold, MD, can be reached at 790 Concourse Parkway South, Suite 200, Maitland, FL 32751; email: rsgeye@gmail.com.
• Nathan M. Radcliffe, MD, can be reached at New York Eye Surgery Center, 1101 Pelham Parkway North, Bronx, NY 10469; email: drradcliffe@gmail.com.
• Michael X. Repka, MD, MBA, can be reached at Johns Hopkins Wilmer Eye Institute, 600 N. Wolfe St., Baltimore, MD 21287; email: mrepka@jhmi.edu.
• Darrell E. White, MD, can be reached at SkyVision Centers, 2237 Crocker Road, Suite 100, Westlake, OH 44145; email: dwhite@healio.com.

Disclosures: Chambers reports no relevant financial disclosures. Devgan reports he is a paid speaker and consultant for Novartis. Gold reports no relevant financial disclosures. Radcliffe reports relevant financial disclosures for Allergan, Novartis, Aerie, Shire and Eyenovia. Repka reports no relevant financial disclosures. White reports he is a consultant and speaker for Allergan and a consultant and speaker for Novartis.

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