As practicing optometrists, we see patients every day with symptoms of dry eye disease. Nearly 30 million Americans report symptoms consistent with Dry Eye Disease. Only 1.5 million are currently being treated with medication.
According to the Tear, Film, and Ocular Surface Society’s (TFOS) latest Dry Eye Workshop (DEWS) II report in 2017, dry eye disease is “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”
Inflammation is a major factor in dry eye and is primarily mediated by T helper cells (CD4+). It can be due to 1) aqueous deficiency (caused by lymphocytic infiltration of the lacrimal gland), or 2) evaporation of the tear layer (caused by meibomian gland dysfunction due to reduction in the lipid component of the tear film).
A number of medications are currently available for the management of signs of ocular surface disruption and/or symptoms of irritation, burning, etc. These treatments suppress inflammatory mediators on the ocular surface, which restores a healthier tear film and reduces signs and symptoms in patients.
There are currently three pharmacotherapies widely available. It is important to understand the mechanisms, clinical trials, and differences and similarities between these drugs so we can make an educated opinion on what will benefit our patients most.
Restasis review
Launched by Allergan in 2003, Restasis was the first medication approved by the FDA for dry eye disease.
Restasis is a 0.05% cyclosporine ophthalmic solution. Cyclosporine is a lipophilic molecule that acts as an immunosuppressant by inhibiting T-cell-mediated inflammation and cytokines in the conjunctiva by stimulating natural tear production and increasing goblet cell density (production and secretion of mucins that lubricates the ocular surface).
The vehicle in Restasis eye drops is Refresh Endura, which allows the patient to feel immediate relief upon instillation of the drop.
Dosage
- Dosed at one drop, twice a day in both eyes. Twelve hours apart. This medication comes in vials and preservative-free multidose bottle.
Restasis side effects
- The most common side effect was ocular burning (17%). Fewer than 5% of patients reported conjunctival hyperemia, discharge, epiphora, and blurred vision.
Clinical trials
- Four clinical studies demonstrated a significant increase in Schirmer wetting and a decrease in ocular staining versus vehicle at six months.
Other studies
- A recent study by Stevenson compared different concentrations of Cyclosporine (0.05%, 0.1%, 0.2%, and 0.4%) versus vehicle-CSa 0.05% produced the most significant improvement in patient symptoms, whereas 0.2% scored the highest in Ocular Surface Disease Index (OSDI; a measure of symptom frequency and impact on vision-related functioning).
Xiidra review
Novartis launched Xiidra eye drops in 2016. As a lifitegrast molecule, Xiidra inhibits the release of pro-inflammatory cytokines.
Studies show that when the tear film is altered, the ocular surface expresses a ligand known as intercellular adhesion molecule-1 (ICAM-1). These fingerlike projections have binding sites for T-lymphocytes. T-lymphocytes have cell surface proteins called LFA-1 integrin. Once LFA-1/ICAM-1 interaction occurs, it causes T-cell activation and migration to target tissues (such as the conjunctiva or lacrimal glands) which leads to a release of inflammatory cytokines. Lifitegrast is an integrin antagonist that blocks the binding of ICAM-1 to LFA-1 on the T-cell surface, inhibiting the recruitment of T cells, causing an interruption in the cycle of inflammation.
Dosage
- Dosed at one drop, twice a day in both eyes. Twelve hours apart. This medication comes in vials only.
Xiidra side effects
- The most common side effects in 5-25% of patients include site irritation, reduced visual acuity, and an unusual taste sensation (dysgeusia). Less than 5% of patients report conjunctival hyperemia, discharge, itchy eyes, and sinusitis.
Clinical trials
- Four clinical trials were conducted to compare Liftergrast 5% to vehicle in 12-week trials. Xiidra reduced symptoms of eye dryness at two weeks in two out of the four studies, and at six and 12 weeks in all four studies. It also improved signs of inferior corneal staining at 12 weeks in three of those studies.
Cequa review
Sun Pharma launched Cequa eye drops in late 2019, clinically referred to as OTX-101, the highest FDA-approved concentration at 0.09% cyclosporine ophthalmic solution.
Cyclosporine is a calcineurin (enzyme that activates T cells) inhibitor. The formula for Cequa encapsulates cyclosporine within nanomicelles (NCELL) to improve the delivery and penetration of cyclosporine to ocular tissues.
The exact mechanism of cyclosporine is not known. However, the idea is that it increases tear production by acting as a partial immunomodulator. Once the NCELL is assembled, the nanomicelle has a hydrophilic outer shell that interacts with the aqueous tear film and a hydrophobic core that only releases the cyclosporine once the nanomicelle penetrates into the ocular tissue.
Compared to other cyclosporine emulsions, this formulation provides 3x more penetration into the ocular tissue, and 1.6x more conjunctival absorption.
Dosage
- Dosed at one drop, twice a day in both eyes. Twelve hours apart. This medication comes in vials only.
Cequa side effects
- Greater than 5% of patients reported pain upon the instillation of drops (22%) and conjunctival hyperemia (6%). Less than 5% of patients reported ocular irritation, blepharitis, and headaches.
Clinical trials
- Phase 2b/3: OTX-101 0.09% and OTX-101 0.05% was compared to vehicle from baseline to 84 days. Both concentrations of OTX-101 improved the primary endpoint of conjunctival staining. Secondary end-points (Schirmer score, tear break up time, corneal staining) also showed improvement in OTX-101. The global symptom score which measured patient frequency and severity of disease was reduced in all treatment groups.
- Phase 3: OTX-101 0.09% was compared to vehicle and showed an increase in Schirmer score after 12 weeks, and corneal and conjunctival staining after four weeks.
Should I start with Cequa, Restasis, or Xiidra?
In a perfect world, doctors would have the choice to choose what drugs they can prescribe. Unfortunately, insurance companies sometimes dictate which option we can start with first. Some insurances would like failure with artificial tears, and/or steroids before approval of a medication. Typically, Restasis or Xiidra are primarily covered. Since Cequa is a newer medication, it may require failure of both Restasis and Xiidra before approval.
Talk to your reps to discuss what current promotion is available for each medication.
Restasis and Cequa are similar drugs, but with different concentrations of cyclosporine and vehicles. They both indicate an increase in tear production. In reference to Stevenson’s study, increasing the percentage of CsA does not correlate with increased efficacy. The vehicles in both drugs are however different, with Cequa boasting an increase in penetration in the ocular tissue due to its NCELL technology. There are no current studies that directly compare the results of Restasis vs Cequa.
On the other hand, Xiidra targets the circle of chronic inflammation in dry eye disease. Some doctors have used both CsA and Liftergrast concurrently.
Fortunately, the representatives of these companies often supply a good amount of samples to trial with patients to make sure the side effects are not bothersome. In my experience, the adverse effects and lack of symptomatic relief are typically the top two reasons why patients discontinue their medication.
I, personally, start with checking for patient coverage, choosing a drug that is in their plan, and then monitoring the patient on a two-to-three month basis. If I don’t see long-term improvement in Schirmer, fluorescein, and/or patient symptoms, I switch to an alternative. Based on the mechanisms discussed above, you can judge what drug to start your patient’s journey with first.
Other treatment options for dry eye disease
Many more anti-inflammatory medications are in the development or clinical trials phases. Beyond the above mentioned, there are various other options available, including but not limited to:
- Steroids: short term therapy that may be used alone or concomitantly
- EYSUVIS (KPI-121 0.25%) from Kala pharmaceuticals is a low dose Loteprednol with mucus-penetrating particle technology which will be undergoing FDA approval in the first half of 2020
- Punctal plugs
- Amniotic membranes
- Autologous serum drops: Serum containing bioactive agents (albumin, vitamin A, anti-inflammatory cytokines) that may promote healthy cell growth and healing of the ocular surface.
- Lacrisert
- Compounded cyclosporine (generic)
- Systemic Omega 3 fatty acids: be cognizant of the dosage of EPA and DHA
- Treatment of concomitant lid disease with scrubs, topical antibiotics, and/or systemic antibiotics
Here’s a 36 page guide on understanding dry eye and meibomian gland dysfunction. Learn how you can treat MGD using LipiFlow, and how to bring this technology to your practice.
Final thoughts on these dry eye medications
A thorough history and investigation are always necessary to identify the cause of dry eye disease. Useful tests include fluorescein or lissamine dye, Schirmer test, and tear break up time (TBUT). Management depends on the accurate diagnosis and severity of the case. Basic treatments include over-the-counter artificial tears, gels, ointments, and diet.
Since dry eye disease is a chronic inflammation of the eye, it is important to start a patient on advanced modalities and follow up routinely to make sure the signs and symptoms are being managed well. There are a vast array of options currently available, with new ones on the horizon. It is imperative for optometrists to be at the frontline of treating dry eye disease in their afflicted patients.
