Continuing Education Activity

Latanoprost is an eye drop formulation for treating elevated intraocular pressure (IOP) in ocular hypertension or open-angle glaucoma patients. It is a prostaglandin F2 alpha analog. Prostaglandins are most commonly used as the first line of treatment in glaucoma due to their efficacy in reducing the IOP, convenient once-daily dosing, and acceptable safety profile. In addition, the fixed-dose combination of netarsudil/latanoprost was approved by the US FDA in March 2019 for open-angle glaucoma and ocular hypertension. This activity covers the mechanism of action, pharmacology, indications, adverse event profiles, contraindications, toxicity, and its management for latanoprost. In addition, it highlights the role of the interprofessional team in the management of conditions where latanoprost holds therapeutic value.

Objectives:

• Describe the different proposed mechanisms of action of latanoprost in the ocular tissue.
• Summarize the recommended dosing technique for latanoprost therapy.
• Review the adverse event profile for latanoprost therapy.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with latanoprost.

Indications

Latanoprost is a United States Food and Drug Administration (FDA) approved eye drop formulation to treat elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. It is a prostaglandin F2 alpha analog. It reduces IOP by increasing the outflow of aqueous humor by improving the uveoscleral outflow.[1]

Prostaglandins are most commonly used as the first line of treatment in glaucoma due to their efficacy in reducing the IOP, convenient once-daily dosing, and acceptable safety profile. Latanoprost is the first prostaglandin analog approved by the United States Food and Drug Administration (FDA). The drug was FDA approved for ocular use in 1996.

Latanoprost is used off-label for different variants of glaucoma, including[2]:

• Pediatric glaucoma
• Chronic angle-closure glaucoma
• Normal-tension glaucoma
• Steroid-induced glaucoma
• Pigmentary glaucoma

In addition, the fixed-dose combination (FDC) of netarsudil/latanoprost was approved by the USFDA in March 2019 for open-angle glaucoma (OAG) and ocular hypertension (OHT).[3]

Mechanism of Action

Prostaglandin synthesis occurs in the cell from arachidonic acid. Arachidonic acid, a 20-carbon molecule, gets metabolized to leukotrienes (LT) by lipoxygenases or converted to cyclic endoperoxides by cyclooxygenases. The cyclic endoperoxides are metabolized to prostaglandin (PG) F2 alpha by prostaglandin synthase and reductase and to thromboxanes by thromboxane synthase.

Prostaglandin, thromboxane, and leukotriene are called eicosanoids. Various receptors exist for eicosanoids, including DP (prostaglandin D), EP (prostaglandin E), FP (prostaglandin F), IP (prostaglandin I or prostacyclin receptor), and TP (prostaglandin T). FP receptor has 2 variants- type A (full-length variant) and type B (spliced variant). Both FP receptors act as G-protein coupled receptors. FP receptors express in multiple ocular tissues, including ciliary smooth muscles.  

Latanoprost is a prostaglandin F2-alpha analog (FP receptor agonist) that increases the uveoscleral outflow of the aqueous. Other prostaglandin F2 alpha analogs with the same mechanism of action are travoprost and tafluprost. The proposed mechanisms include[4][5]:

• Relaxation of ciliary smooth muscles
• Cytoskeletal alteration leads to change in the shape of cells
• Remodeling of the extracellular matrix of the uveoscleral pathway by increased matrix metalloproteinases
  • PG F 2alpha and latanoprost were noted to reduce collagen I, III, and 4, hyaluronans, fibronectin, and laminin; and increase matrix metalloproteinases 2 and 3 and plasmin in cultured ciliary smooth muscles.
  • In the animal model, researchers noted that topical PGF2 alpha reduces the expression of TIGR (trabecular meshwork inducible glucocorticoid response gene) or MYOC (myocilin).

Pharmacokinetics

• Absorption: Latanoprost is absorbed through the cornea. The isopropyl ester of latanoprost gets hydrolyzed by the cornea to the acid, which is the biologically active form. Studies in men indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration. The maximum drug concentration in the aqueous humor is achieved 2 hours after topical use of the drop. The drug starts reducing IOP after 3 to 4 hours of administration, and the maximum IOP lowering effect is seen 8 to 12 hours after use. The IOP lowering effect lasts for more than 24 hours, allowing once-daily dosage. 

• Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The solubility of latanoprost, travoprost, and unoprostone improves by adding isopropyl ester to the carboxyl-terminal of PG F 2 alpha. The addition of a phenyl ring to the omega chain of PG F 2 alpha in the prostaglandin analogs (latanoprost, travoprost, bimatoprost) improves selectivity for the FP receptor. In animal studies, topical PG in high doses showed an initial IOP rise with a subsequent prolonged period (15 to 20 hours) of IOP reduction. A high dose may also disrupt the blood-aqueous barrier and cause conjunctival hyperemia. On the other hand, low-dose topical PG causes prolonged IOP reduction only.[6]

• Metabolism: Latanoprost is an isopropyl ester prodrug. Esterases hydrolyze the prodrug in the cornea to the biologically active acid. The liver metabolizes the latanoprost reaching the systemic circulation to the 1,2-dinor and 1,2,3,4-tetranor by fatty acid β-oxidation.

• Excretion: Latanoprost elimination from human plasma is rapid (t1/2 = 17 min) after intravenous and topical administration. Systemic clearance is 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the given dose are recovered in the urine after topical and IV dosing, respectively.

• In animal studies, topical PG in high doses showed an initial IOP rise with a subsequent prolonged period (15 to 20 hours) of IOP reduction. A high dose may also disrupt the blood-aqueous barrier and cause conjunctival hyperemia. On the other hand, low-dose topical PG causes prolonged IOP reduction only.[6]

Administration

Latanoprost is available as a colorless, isotonic ophthalmic solution at a strength of 0.005%. According to the manufacturer, unopened bottles should be stored 'under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). During shipping, the container may remain at temperatures up to 40 degrees C (104 degrees F) for a period not to exceed eight days. Upon opening the bottle, it may be stored at room temperature up to 25 degrees C (77°F) for six weeks.

The dosage is one drop once daily at night, and curiously the IOP lowering effect reduces (or paradoxical IOP rise may occur) when used more than once daily. The reduction in the IOP lowering effect may be due to subsensitivity at the FP receptors.[7]

Latanoprost may be administered with other antiglaucoma agents to reduce intraocular pressure. If using more than one topical ophthalmic drug, there should be a minimum gap of 5 minutes between two drops. Contact lenses require removal before administering the medication, and the patient should not reinsert them within 15 minutes of the topical application of the drop. Latanoprost administration is topical, with one drop once daily in the evening in the affected eye/s.

The average IOP drop with latanoprost is in the range of 30% to 35%. At six months, latanoprost was noted to reduce IOP by 35% when applied in the evening and 31% when instilled in the morning compared to timolol, which caused a 27% reduction of IOP.[8] A meta-analysis found that the mean IOP reduction in mm of Hg with various antiglaucoma drugs was - bimatoprost 5.61, latanoprost 4.85, travoprost 4.83, levobunolol 4.51, tafluprost 4.37, timolol 3.70, brimonidine 3.59, carteolol 3.44, levobetaxolol 2.56, apraclonidine 2.52, dorzolamide 2.49, brinzolamide 2.42, betaxolol 2.24, and unoprostone 1.91.[9]

Once-daily latanoprost has been shown to achieve a uniform round-the-clock reduction of IOP either alone or combined with a twice-daily dose of timolol.[10] The dosage is once daily when using a combination drop of latanoprost and timolol.

Use in Specific Population

• Patients with Hepatic Impairment: There is no information about dosage adjustments in patients with hepatic impairment in the manufacturer's labeling.

• Patients with Renal Impairment: There is no information about dosage adjustments in patients with renal impairment in the manufacturer's labeling.

• Pregnancy Considerations: Prostaglandins stimulate uterine smooth muscle, inducing uterine contractions, and animal studies have indicated an augmented risk of abortion or preterm delivery. In animal reproduction studies, intravenous (IV) administration of latanoprost to pregnant rabbits and rats throughout organogenesis resulted in embryofetal lethality, malformations, and spontaneous abortion at clinically relevant doses. There are no adequate and well-controlled studies of latanoprost ophthalmic solution administration in pregnant women to advise regarding drug-associated risks. However, theoretically, prostaglandins increase uterine tone and can lead to premature labor. Hence, other classes of medications than latanoprost should be selected to treat glaucoma during pregnancy. (FDA Category C)[11][12]

• Breastfeeding Considerations: No information is available on the use of latanoprost during breastfeeding. Because of its short half-life, it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. Professional guidelines consider prostaglandin eye drops acceptable during breastfeeding. To diminish the amount of drug that reaches the breastmilk after using eye drops, the clinician should advise the patient to place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue.[13]

Adverse Effects

The primary adverse effects of latanoprost include eyelid edema, blurred vision, dry eyes, itching, redness, the growth of eyelashes, change in eyelid pigmentation (may become darker), iris, and eyelash.

• Conjunctival Hyperemia: Conjunctival hyperemia is one of the most common side effects noted in 5% to 15% of patients, more than in timolol-treated eyes. Latanoprost with preservative (benzalkonium chloride) may reduce the goblet cell density.[14] The conjunctival redness usually appears within 2 to 3 days of initiation of the topical treatment, reduces within one month, and is typically mild with prolonged use.

• Hypertrichosis: Hypertrichosis is an increase in the thickness, length, and number of eyelashes. Although this is preferred from a cosmetic point of view in some patients, the unilateral occurrence can be undesirable. The changes in the eyelashes are usually reversible after discontinuation of the drug; this is due to the stimulation of the growth phase of the hair cycle.[1]

• Pigmentation: The pigmentation is due to increased melanin in the melanocytes, but the number of melanocytes does not increase. There is an upregulation of the tyrosinase activity in the melanocytes.[15] The pigmentation may increase for the duration of drug use. The brownish color change of the iris after latanoprost use is permanent, but the pigmentation of the eyelid, periorbital tissue, and eyelash may be reversible. The pigmentation of the iris usually starts around the pupillary margin and then spreads towards the peripheral iris. Iris nevi and freckles are not affected by latanoprost. The pigmentation of the iris usually begins within one year of therapy and continues to increase with the use of the drug. Patients should receive counsel regarding the possible change in iris color, which may be more evident if using the medicine in only one eye. The iris pigmentation is more common in light-colored rides but may also occur in dark or brown rides. Darkening of the iris may occur in up to 10% of cases. Pigmentation of periocular tissue is reducible by removing the excess latanoprost drop from around the eye.[15]

• Intraocular Inflammation: Latanoprost may worsen intraocular inflammation (uveitis) and should be avoided in the actively inflamed eye. 

• Macular Edema: Latanoprost may induce or aggravate macular edema, including cystoid macular edema. Patients with aphakia and pseudophakia with open posterior capsules are at higher risk of developing cystoid macular edema(CME).[16] Prostaglandin analogs(PGA) related to CME can be treated with discontinuation of the PGA. The most commonly used treatment strategy in pseudophakic CME is to suppress postsurgical inflammation using topical NSAIDs or corticosteroids, either separately or combined. Corticosteroids are commonly used to treat pseudophakic CME because of their well-known anti-inflammatory effects.[16]

• Reactivation of herpetic keratitis: may occur with latanoprost, and patients with active herpetic keratitis should avoid latanoprost.[17] A contaminated multidose vial of latanoprost may cause bacterial keratitis in patients with a corneal epithelial defect or other corneal diseases.

• Superficial punctate keratopathy: Damage to the ocular surface, including reduced tear break-up time, superficial punctate keratopathy may occur due to the preservative in latanoprost (benzalkonium), and the ocular surface toxicity has been noted to be less with preservative-free tafluprost.[18]

• Other side effects of latanoprost include contact dermatitis/allergic conjunctivitis and iris cyst.[19]

Contraindications

According to product labeling, latanoprost is contraindicated in patients with documented hypersensitivity to the drug or components of the formulation. The components of the drop include latanoprost (the active ingredient). Inactive ingredients include benzalkonium chloride (preservative), sodium chloride, monobasic sodium phosphate, and dibasic sodium phosphate.

Monitoring

Monitor for adverse drug reactions such as intraocular inflammation, pigmentary changes, and macular edema. Monitor intraocular pressure every 2 to 4 weeks until target intraocular pressure is attained. Subsequently, every six months is sufficient. 

For pediatric glaucoma, a 14-day home monitoring period provided a more than 90% chance of identifying an IOP spike.[20]

Toxicity

Researchers found it to cause no carcinogenesis or mutagenesis and not affect fertility in animal studies. However, latanoprost was noted to cause a chromosomal aberration in treated human lymphocytes. Intravenous infusion of 3 mcg/kg of latanoprost in healthy volunteers produced plasma concentrations 200 times higher than during clinical treatment with latanoprost ophthalmic solution, and researchers identified no ADR. Presently, there are no evidences to establish a corelation between latanoprost administartion with ocular or cutaneous melanoma.[21] Intravenous infusion of 5.5 to 10 mcg/kg resulted in fatigue, sweating, dizziness, nausea, and abdominal pain. Therefore, according to the manufacturer's labeling, treatment should be symptomatic if there is an overdosage with latanoprost ophthalmic solution.

Enhancing Healthcare Team Outcomes

Latanoprost is one of the prostaglandin analogs, considered the first-line management of open-angle glaucoma. Multiple randomized control trials have proven its efficacy in lowering IOP in primary open-angle glaucoma, which is similar to travoprost, and bimatoprost, but the tolerability of latanoprost may be better (Level I).[22][1] Retinal examination for cystoid macular edema and ruling out active inflammation before starting the therapy is vital. Also, the IOP should be monitored by the ophthalmologist and the ophthalmic specialty-trained nurse regularly to ensure that the medication is working. The pharmacist should educate the patient about the adverse effects of the drug, which may include darkening of the color of the iris, eyelids, periocular area, and eyelashes.[22]

An interprofessional team approach is needed to provide comprehensive and collaborative care for the patient. The ophthalmology-trained nurse and the pharmacist play a crucial role in assisting the clinician in achieving this goal. The nurse can assist the clinician in educating the patient about the indication and expected outcomes of latanoprost therapy and the need for following up on IOP testing. The pharmacist can help the team by educating the patient about proper dosing, administration, storage, and adverse effects of the drug to ensure its efficacy. Collaboration and communication across these disciplines in an interprofessional team approach can achieve the best outcomes with latanoprost therapy. [Level V]