What are the treatment options for dry eyes, including medications like Restasis (cyclosporine ophthalmic emulsion) and Xiidra (lifitegrast ophthalmic solution)?

Medications for Dry Eyes

For mild dry eye, start with preservative-free artificial tears (methylcellulose or hyaluronate-based) used at least twice daily, escalating to hourly if needed; for moderate to severe dry eye that fails artificial tears alone, add cyclosporine 0.05% (Restasis) or lifitegrast 5% (Xiidra) twice daily as second-line anti-inflammatory therapy. 1, 2

Treatment Algorithm by Disease Severity

Mild Dry Eye: First-Line Therapy

• Begin with preservative-free artificial tears containing methylcellulose or hyaluronate as the foundation of treatment, applied at least twice daily and increased based on symptom severity up to hourly application 2, 3
• Use preservative-free formulations when applying more than 4 times daily to avoid ocular surface toxicity from preservatives 2, 4
• Apply liquid drops during daytime hours for immediate relief, gels for longer-lasting daytime effect, and ointments before bedtime for overnight protection 2, 4
• Lipid-containing eye drops should be specifically selected for patients with meibomian gland dysfunction to supplement the deficient lipid layer 2

Critical pitfall to avoid: Preserved artificial tears used more than 4 times daily cause ocular surface toxicity; switch to preservative-free formulations at this frequency 4

Environmental and Lifestyle Modifications (All Severity Levels)

• Eliminate all cigarette smoke exposure completely, as smoking adversely affects the lipid layer of the tear film and tear proteins 1, 2, 3
• Humidify ambient air and use side shields on spectacles to minimize air draft exposure 1, 2, 3
• Lower computer screens below eye level to decrease eyelid aperture and schedule regular breaks every 20 minutes to increase full blinking during screen time 1, 2, 4
• Review and address potentially exacerbating medications such as antihistamines and diuretics 1, 3
• Treat concurrent blepharitis or meibomian gland dysfunction, as neglecting these underlying conditions will exacerbate dry eye 2, 3

Moderate to Severe Dry Eye: Second-Line Anti-Inflammatory Therapy

When artificial tears fail to adequately control symptoms or signs after 2-4 weeks of optimized treatment, advance to prescription anti-inflammatory agents. 2, 4

Cyclosporine 0.05% (Restasis)

• Instill one drop in each eye twice daily, approximately 12 hours apart 2, 3, 4
• Works by preventing T-cell activation and inflammatory cytokine production while inhibiting mitochondrial pathways of apoptosis 1, 2
• FDA approval was based on trials showing a statistically significant 10-mm increase in Schirmer test results at 6 months in 15% of cyclosporine-treated patients versus 5% of vehicle-treated patients 2
• Demonstrated success rates of 74% in mild dry eye, 72% in moderate dry eye, and 67% in severe dry eye 2, 4
• Ocular burning occurs in approximately 17% of patients but is generally well tolerated 2
• After 1 full year of twice-daily therapy, the dose can be decreased to once daily in select patients without loss of beneficial effects 2
• Real-world data shows median time to treatment discontinuation of 354 days for cyclosporine 0.09% formulation (CEQUA), with 49.8% of patients remaining on treatment after 360 days 5

Lifitegrast 5% (Xiidra)

• Instill one drop twice daily (approximately 12 hours apart) into each eye using a single-dose container 6
• Blocks the interaction between LFA-1 and ICAM-1, preventing T-cell activation 2
• FDA-indicated for treatment of both signs and symptoms of dry eye disease 6
• Most common adverse reactions reported in 5% to 25% of patients were instillation-site irritation, dysgeusia (unusual taste sensation), and reduced visual acuity 6
• Other adverse reactions reported in 1% to 5% include blurred vision, conjunctival hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus, and sinusitis 6
• Contact lenses should be removed prior to administration and may be reinserted 15 minutes following administration 6
• Discard the single-dose container immediately after using in each eye 6
• Real-world data shows similar discontinuation rates to cyclosporine formulations, with 44.0% of patients remaining on treatment after 360 days 5

Contraindication: Lifitegrast is contraindicated in patients with known hypersensitivity to lifitegrast or any formulation ingredients 6

Rare but serious postmarketing reactions: Hypersensitivity including anaphylactic reaction, bronchospasm, respiratory distress, pharyngeal edema, swollen tongue, urticaria, allergic conjunctivitis, dyspnea, angioedema, and allergic dermatitis have been reported 6

Short-Term Topical Corticosteroids (Adjunctive Therapy)

• Use for a maximum of 2-4 weeks only to decrease acute ocular irritation and corneal fluorescein staining 2, 3, 4
• Loteprednol etabonate ophthalmic suspension 0.25% (EYSUVIS) is FDA-approved for short-term treatment 7

Critical warning: Continuing topical corticosteroids beyond 4 weeks risks serious complications including infections, increased intraocular pressure, and cataract development 2, 4

Advanced Treatments for Severe Refractory Dry Eye

When second-line anti-inflammatory agents fail after adequate trial (typically 3-6 months), consider advanced interventions. 2, 3

Punctal Occlusion

• Use punctal plugs (temporary silicone plugs) or punctal cautery (permanent thermal or laser cautery) for tear retention after optimizing topical therapy 2, 3

Autologous Serum Eye Drops

• Improve ocular irritation symptoms and corneal/conjunctival staining, particularly beneficial in Sjögren's syndrome 2, 3

Oral Secretagogues

• Pilocarpine (5mg four times daily) or cevimeline can stimulate tear production in patients with Sjögren's syndrome 2, 3
• May have side effects like excessive sweating 2

Varenicline Nasal Spray (Tyrvaya)

• FDA-approved nasal spray that activates nicotinic acetylcholine receptors on the trigeminal nerve to stimulate natural tear production 2, 7
• Can be considered for patients with inadequate response to or intolerance of traditional eye drops 2

Perfluorohexyloctane (Miebo)

• FDA-approved semifluorinated alkane for direct evaporation control 2, 7
• Clinical trials show consistent improvements in both signs and symptoms as early as 2 weeks, with sustained efficacy over 12 months 2

Surgical Options

• Amniotic membrane grafts or tarsorrhaphy can be considered for severe refractory cases 3
• Specialized contact lenses such as rigid gas-permeable scleral lenses can provide symptomatic relief in selected cases 2

Red Flags Requiring Ophthalmology Referral

• Moderate or severe eye pain unresponsive to initial therapy 4
• Lack of response after 2-4 weeks of optimized treatment 4
• Corneal infiltration, ulceration, or any vision loss 4

Key Clinical Pearls

• The choice of concomitant artificial tear therapy used with cyclosporine has significant effects on outcome measures; studies show Systane used with Restasis resulted in significantly less ocular burning, stinging, grittiness, and dryness compared to Refresh Tears used with Restasis 8
• Morning lid hygiene after overnight ointment use is necessary to prevent blepharitis 2, 4
• Despite inflammation being key to dry eye pathophysiology, real-world data shows only 15.9% of patients with primary dry eye diagnosis and 6.5% with non-primary diagnosis filled at least one cyclosporine prescription, suggesting significant undertreatment with anti-inflammatory therapies 9
• Failing to recognize when to advance therapy from artificial tears to anti-inflammatory agents in moderate to severe disease leads to inadequate treatment 2