VA Class:OP109
ATC Class:S01EE01
Latanoprost, a synthetic analog of naturally occurring prostaglandin F2α (PGF2α), is an ocular hypotensive agent.1, 2, 3, 32, 33
Ocular Hypertension and Glaucoma
Latanoprost ophthalmic solution or ophthalmic emulsion is used topically to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.1, 3, 10, 11, 12, 13, 15, 30, 31, 32, 33, 48, 55, 60, 90 Netarsudil and latanoprost fixed-combination ophthalmic solution also is used topically to reduce elevated IOP in patients with open-angle glaucoma or ocular hypertension.91 Elevated IOP presents a major risk factor in glaucomatous field loss; the higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.1
Elevated IOP in patients with glaucoma can be reduced by medical treatment, laser therapy, and/or incisional glaucoma surgery; treatment with a topical ocular hypotensive agent frequently is the initial intervention for primary open-angle glaucoma.130 Selection of an initial ocular hypotensive agent is influenced by the extent of the required reduction in IOP, coexisting medical conditions, and the characteristics of the individual drugs (e.g., dosing frequency, adverse effect profile, cost).130, 132 With single-agent regimens, the reduction in IOP is approximately 25-33% with topical prostaglandin analogs; 20-25% with topical β-adrenergic blocking agents, α-adrenergic agonists, or miotic (parasympathomimetic) agents; 20-30% with oral carbonic anhydrase inhibitors; 18% with topical rho kinase inhibitors; and 15-20% with topical carbonic anhydrase inhibitors.130, 131 In the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal), a prostaglandin analog frequently is considered for initial therapy because of the relatively greater activity, once-daily administration, and low frequency of systemic adverse effects with this drug class; however, ocular adverse effects can occur.130, 131, 132, 134
IOP should be reduced toward a target level that the clinician believes will slow disease progression and avoid visual field losses that would substantially reduce quality of life during the patient's lifetime.130, 132 The target level is an estimate and should be individualized based on such factors as the extent of optic nerve damage and/or visual field loss, the baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations.130, 132 Reducing the pretreatment IOP by 25% or more has been shown to slow progression of primary open-angle glaucoma.130, 131 The target IOP should be adjusted up or down as needed over the course of the disease.130, 131, 132 If the target IOP is not achieved with single-agent therapy, alternative or additional ocular hypotensive agents may be selected depending on the patient's response to the initial drug.130 Combination therapy with drugs from different therapeutic classes often is required to achieve adequate control of IOP.131, 133
Like topical β-adrenergic blocking agents, latanoprost reduces elevated IOP in patients with open-angle glaucoma without producing miosis and/or ciliary spasm that are associated with miotic agents.3, 11, 30 Although use of some topical β-adrenergic blocking agents (e.g., levobunolol, timolol) may be associated with adverse pulmonary and cardiovascular effects, these adverse systemic effects also have been reported with latanoprost.1, 10, 11, 12, 13, 30, 49
Latanoprost is highly effective in reducing IOP when used alone or in conjunction with other ocular hypotensive agents.10, 11, 12, 36 In phase 3 studies in patients with open-angle glaucoma or ocular hypertension, less than 1% of patients receiving latanoprost alone dropped out of the studies because of inadequate IOP response to the drug.10, 11, 12
Safety and efficacy of latanoprost have been evaluated in several multicenter, randomized, double-blind, active-controlled studies that involved several hundred patients with open-angle glaucoma or ocular hypertension.1, 3, 10, 11, 12, 15, 30, 31, 32, 33, 36, 48 In these studies, which included patients with mean baseline IOP values of 23-25 mm Hg, topical application of latanoprost 0.005% once daily for up to 12 months reduced IOP by 6.3-8.6 mm Hg which corresponds to a 27-35% reduction in IOP from baseline values.1, 3, 10, 11, 12, 15, 30, 32, 33, 36
Latanoprost appears to be more effective than unoprostone (no longer commercially available in the US), as effective as travoprost, and slightly less effective than bimatoprost in reducing IOP in patients with open-angle glaucoma or ocular hypertension.76, 77, 78, 79, 80, 81 In several randomized, comparative studies, once-daily administration of latanoprost 0.005% was associated with greater reductions in IOP than twice-daily administration of unoprostone 0.12-0.15%.81, 82, 83, 84, 85 Latanoprost appears to be slightly less effective than bimatoprost in reducing IOP or achieving target IOP.76, 77, 78 In several multicenter, randomized, comparative studies, once-daily administration of latanoprost 0.005% was associated with slightly smaller reductions in IOP than once-daily administration of bimatoprost 0.03% but the differences were not always statistically significant;78, 79 however, in one study, reductions in IOP following latanoprost were significantly smaller than those achieved with bimatoprost.76 In addition, data from most comparative studies indicate that latanoprost generally is less effective than bimatoprost in achieving target IOP (particularly lower target IOP); in these studies, target IOP was achieved in fewer patients receiving latanoprost compared with those receiving bimatoprost.76, 77, 78 Although slightly less effective than bimatoprost, treatment with latanoprost was associated with a lower incidence of conjunctival hyperemia than treatment with bimatoprost.76, 78
Once-daily administration of latanoprost 0.005% appears to be more effective or at least as effective as twice daily administration of timolol 0.5% in reducing IOP in patients with open-angle glaucoma or ocular hypertension.1, 3, 10, 11, 12, 30, 31, 32, 33 In one comparative study in patients with mean baseline IOP of 24.6-25.5 mm Hg who received latanoprost 0.005% once daily or timolol 0.5% twice daily, 69% of those who received latanoprost had a diurnal IOP (defined as the average of IOPs determined at 8 am, 12 noon, and 4 pm) of 17 mm Hg or lower at the end of the 6-month study compared with 34% of those who received timolol during the same period.10 Once-daily administration of latanoprost 0.005% appears to be more effective than thrice-daily administration of dorzolamide 2%.86, 87
Studies to date indicate that tolerance to latanoprost does not occur and that the reduction in mean IOP is maintained for up to at least 24 months of therapy after initial stabilization.3, 10, 11, 12, 15, 36, 44, 48
In 2 randomized, controlled clinical trials evaluating the fixed-combination ophthalmic solution of netarsudil 0.02% and latanoprost 0.005% in adults with open-angle glaucoma or ocular hypertension (baseline IOP less than 36 mm Hg), the mean reduction in IOP achieved with once-daily administration of the fixed-combination ophthalmic solution was approximately 1-3 mm Hg greater than that achieved with once-daily administration of either drug alone throughout 3 months of treatment.91, 92 The treatment duration was 3 months in one study and 12 months in the other study.91, 92 In the latter study, IOP reductions were maintained throughout 12 months of treatment.91
In one study in patients with open-angle glaucoma or capsular glaucoma receiving timolol 0.5% twice daily in whom IOP was not adequately controlled (i.e., IOP values remained at 22 mm Hg or higher), concomitant use of latanoprost 0.006% once daily resulted in a further decrease in IOP of 32 or 37% at 4 or 12 weeks, respectively.29 While specific data are limited, use of latanoprost in conjunction with dipivefrin (no longer commercially available in the US) or acetazolamide also appears to be more effective in lowering IOP than use of these agents alone.33, 59 In addition, combined therapy with latanoprost and a topical miotic (e.g., pilocarpine) appears to be additive;19, 46, 47, 88, 89 order and timing of administration of pilocarpine relative to latanoprost appear to alter ocular hypotensive activity.68
Pigmentation changes in the iris that may be induced by latanoprost do not appear to decrease the drug's efficacy.1 Data from a 3-year open-label study with a 2-year extension phase indicate that clinical response to latanoprost (i.e., reduction in IOP) in patients with an increase in brown pigmentation in the iris as a result of latanoprost therapy is similar to the response in other patients.1 (See Increased Iris Pigmentation under Cautions: Ocular Effects.)
Latanoprost is applied topically to the eye as an ophthalmic solution or emulsion.1, 10, 11, 12, 32, 33, 36, 90 Latanoprost also is commercially available in fixed combination with netarsudil for topical application to the eye as an ophthalmic solution.91 Care should be taken to avoid contamination of the dispensing container.1, 90, 91 (See Cautions: Precautions and Contraindications.)
Latanoprost ophthalmic solution and netarsudil and latanoprost fixed-combination ophthalmic solution contain benzalkonium chloride, which may be absorbed by some contact lenses.1, 91 The manufacturers of latanoprost ophthalmic solution or emulsion and netarsudil and latanoprost fixed-combination ophthalmic solution state that contact lenses should be removed prior to administration of each dose of these preparations but may be reinserted 15 minutes after the dose.1, 90, 91
If the patient is receiving more than one topical ophthalmic preparation, the preparations should be administered at least 5 minutes apart.1, 90, 91
For the treatment of open-angle glaucoma or ocular hypertension, the usual adult dosage of latanoprost is 1 drop of a 0.005% ophthalmic solution or emulsion (1.5 mcg) in the affected eye(s) once daily in the evening.1, 10, 11, 12, 32, 33, 36, 90
If the target intraocular pressure (IOP) is not achieved, alternative or additional ocular hypotensive agents may be required.130, 131, 133 (See Uses: Ocular Hypertension and Glaucoma.) However, concomitant use of 2 or more prostaglandin analogs is not recommended.1, 90, 91 When latanoprost is used in fixed combination with netarsudil, the usual adult dosage is 1 drop of an ophthalmic solution containing netarsudil 0.02% and latanoprost 0.005% in the affected eye(s) once daily in the evening.91
Patients should be instructed that topical ophthalmic preparations containing latanoprost should be applied no more frequently than once daily since more frequent dosing may reduce the IOP-lowering effect of the drug or cause paradoxical elevation of IOP.1, 15, 29, 39, 90, 91 If the patient misses a dose, the usual schedule should be continued with the next dose applied the following evening.1, 15, 90, 91
Latanoprost ophthalmic solution generally is well tolerated following topical application to the eye.3, 10, 11, 12, 30, 32, 33, 36, 48 Discontinuance of latanoprost therapy was required in about 5.1% of patients in clinical studies, principally because of increased iris pigmentation.10, 11, 12, 15, 36 Less than 1% of patients required discontinuance of latanoprost therapy because of conjunctival hyperemia.1, 15
In phase 3 clinical studies evaluating latanoprost ophthalmic solution, the incidence of most adverse ocular effects (e.g., punctate keratopathy, dry eye, blurred vision, excessive tearing, ocular or eyelid discomfort, burning, stinging, itching, foreign body sensation) in patients receiving once-daily topical latanoprost generally was similar to that in patients receiving twice-daily topical timolol.3, 10, 11, 12, 33 While the percentage of patients who experienced increases in conjunctival hyperemia from baseline was slightly higher with latanoprost than with timolol and mean conjunctival hyperemia was graded slightly higher with latanoprost, all cases of hyperemia were graded as mild in severity.10, 11, 12 In one study, mild punctate epithelial keratopathy occurred more frequently in patients receiving latanoprost than those receiving timolol but this was attributed to the higher concentration of benzalkonium chloride (0.02%) in latanoprost ophthalmic solution and vehicle compared with the concentration in timolol ophthalmic solution (0.01%).12, 15
In clinical trials evaluating latanoprost ophthalmic emulsion, less than 1% of patients receiving the drug discontinued therapy because of eye pain/stinging or ocular hyperemia,90 while in clinical trials evaluating netarsudil and latanoprost fixed-combination ophthalmic solution, 5% of patients receiving the fixed-combination ophthalmic solution discontinued therapy because of ocular hyperemia.91
Topical ophthalmic use of latanoprost has been associated with an increase in brown pigmentation of the iris in some patients.1, 3, 10, 11, 12, 15, 31, 32, 33, 36, 48 The increased pigmentation develops slowly, and may not be evident until after several months to years of latanoprost therapy.1, 10, 11, 12, 15, 33, 36 In most affected eyes, brown pigmentation around the pupil gradually spreads concentrically toward the periphery; however, the entire iris or parts of the iris also may become brownish in color.1, 3, 10, 11, 12, 15 Data from a 3-year open-label study with a 2-year extension phase indicate that increased pigmentation in the iris does not affect the incidence, type, or severity of other adverse effects associated with latanoprost therapy or clinical response to the drug.1 Experience in patients receiving latanoprost for up to 5 years indicates that noticeable increased pigmentation generally occurred within the first year of therapy and that pigmentation increases as long as latanoprost is administered.1 While latanoprost therapy can be continued in patients who experience increased pigmentation in the iris, these patients should be examined regularly.1 While the increase in brown pigment generally does not progress further if latanoprost is discontinued, the change in iris color is likely to be permanent.1, 15, 32 The effects of increased pigmentation beyond 5 years remain to be determined.1
In phase 3 clinical studies, increased pigmentation of the iris occurred in approximately 6.8 or 15.5% of patients receiving the drug for 6 or 12 months, respectively.3, 10, 11, 12, 15, 32, 33, 36 Incidence of pigmentation changes varied among clinical study sites, with a 12-month incidence of 22.9% reported in the United Kingdom, 10.9% in Scandinavia, or 8.8% in the US.10, 11, 12, 13, 15, 36 The higher incidence of this effect in the UK study population has been attributed to the greater frequency of irides predisposed to increased pigmentation.10, 11, 12, 15, 36 Increased pigmentation during latanoprost therapy generally occurs in individuals with mixed colored irides (i.e., blue-brown, grey-brown, green-brown, yellow-brown).3, 10, 11, 12, 15, 31, 32, 33, 36 Increased brown pigmentation was not reported in patients with uniform blue, grey, or brown color irides who received latanoprost therapy for 1 year in clinical studies.36
Examination in monkeys and patients experiencing increased pigmentation indicate that this effect is most likely the result of a direct melanogenic effect (i.e., stimulation of melanin production in the melanocytes of the iris) without structural alterations or signs of pathology.1, 3, 12, 15, 31, 32, 33, 36 Iris melanocytes appear to be continent (i.e., do not release pigment to neighboring cells) and pigmentation changes have not been observed in other tissues of the eye, specifically in the trabecular meshwork or choroid.12, 36 Preexisting iris freckles or nevi do not appear to be affected by latanoprost therapy.1, 3, 10, 11, 12, 33, 36
Increased Periorbital Pigmentation and Eyelash Changes
Hypertrichosis and increased pigmentation in lashes and periorbital tissue (eyelid) have occurred following topical application of latanoprost.1, 41, 44, 50, 66, 72, 73, 74 While pigmentation increases as long as latanoprost is administered, these changes have been reversible following discontinuance of the drug in some patients.1, 72 In patients receiving latanoprost ophthalmic solution, hypertrichosis involving terminal lashes, regional intermediate hairs, and vellus hairs was observed in patients receiving the drug for an average of 19 weeks (range: 17-36 weeks).41 Eyelash or vellus hair changes associated with latanoprost therapy include longer, thicker, more numerous, darker lashes or hairs, and misdirected growth of eyelashes.1, 41, 50, 66, 74 In clinical trials evaluating latanoprost ophthalmic emulsion, eyelash growth and thickening were reported in 8-11% of patients receiving latanoprost and eyelash discoloration was reported in 1% of patients receiving the drug.90 Eyelash changes usually are reversible upon discontinuance of latanoprost.1
Blurred vision,1, 3, 10, 11, 12, 30, 32, 33 burning and stinging,1, 3, 5, 10, 11, 12, 30, 32, 33 foreign body sensation,1, 3, 9, 32, 33 itching,1, 3, 11, 12, 30, 33 and punctate epithelial keratopathy1, 3, 10, 11, 12, 32, 33 have been reported in 5-15% of patients receiving latanoprost ophthalmic solution in phase 3 clinical studies. While conjunctival hyperemia1, 3, 9, 10, 11, 12, 17, 20, 30, 32, 33 occurred in 5-15% of patients, less than 1% of patients required discontinuation of the drug because of this adverse effect.1, 15 Conjunctival hyperemia generally is transient, occurring in the first 1-2 days of latanoprost therapy and diminishing after 2-4 weeks of therapy.20, 28, 33 Dry eye,1, 12, 33 excessive tearing,1, 11, 12, 30, 33 eye pain,1, 3, 11, 12 lid crusting,1 lid edema,1, 11, 12 lid erythema,1, 12 lid discomfort/pain,1, 10, 11, 12, 33 or photophobia1, 11, 12 occurred in 1-4% of patients receiving latanoprost ophthalmic solution in phase 3 clinical studies.1
In clinical trials evaluating latanoprost ophthalmic emulsion, eye pain/stinging upon instillation and ocular hyperemia were reported in 55 and 41%, respectively, of patients receiving latanoprost; however; less than 1% of patients required discontinuance of therapy because of these adverse effects.90 Conjunctival hyperemia, eye discharge, and ocular pruritus were reported in 5-15% of patients receiving latanoprost ophthalmic emulsion, and decreased visual acuity, dry eye, lid erythema, foreign body sensation, punctate keratitis, lid edema, and conjunctival edema were reported in 1-4% of patients.90
In controlled clinical trials evaluating netarsudil and latanoprost fixed-combination ophthalmic solution, conjunctival hyperemia was reported in 59% of patients receiving the fixed-combination ophthalmic solution; 5% of patients required discontinuance of therapy because of this adverse effect.91 Instillation site pain, corneal verticillata, and conjunctival hemorrhage were reported in 11-20% of patients receiving the fixed-combination ophthalmic solution, and ocular pruritus, decreased visual acuity, increased lacrimation, instillation site discomfort, and blurred vision were reported in 5-8% of patients.91
Other adverse ocular effects reported in patients receiving latanoprost include conjunctivitis,10, 11, 12, 30 diplopia,11 discharge from the eye,11, 12, 30 allergic reaction,36 keratitis,1 herpes simplex keratitis,1, 70 intraocular inflammation (i.e., iritis/uveitis),1, 52, 53, 54, 57, 64 ocular hypotony,65 corneal edema and erosions,1 choroidal effusions,65 iris cyst,1 localized skin reaction on the lids,1 periorbital and lid changes resulting in deepening of the lid sulcus,1 pseudopemphigoid of ocular conjunctiva,1 and macular edema (including cystoid macular edema).1, 51, 52, 53, 54, 58, 61, 62, 63, 64, 65, 69 Most reports of macular edema occurred in aphakic patients, pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.51, 52, 53, 54, 58, 61, 62, 63, 64, 65, 69
In phase 3 studies, latanoprost therapy was not associated with infiltration of cells into the anterior chamber or changes in aqueous flare intensity.10, 11, 12 In one study evaluating the long-term safety and efficacy of latanoprost in patients who received the drug for 1 year, slight aqueous flare was observed at least once in a few patients and a few cells in the anterior chamber were observed in some patients.36 Compared with baseline, latanoprost therapy has not been associated with substantial changes in visual acuity, refraction, or slit-lamp biomicroscopic examination.3, 10, 11, 12, 33, 36
Latanoprost appears to have a low potential for causing adverse systemic effects when applied topically to the eye.1, 10, 11, 12, 36 Upper respiratory tract infection/nasopharyngitis/influenza has occurred in 3% of patients receiving latanoprost ophthalmic solution in phase 3 clinical studies.1, 12, 33 Adverse systemic effects reported in 1-2% of patients receiving latanoprost in these studies include muscle/joint/back pain1, 10, 12, 33 and rash/allergic skin reactions.1, 10, 33, 65
Other systemic adverse effects reported in patients receiving latanoprost include toxic epidermal necrolysis,1 pruritus,1 edema (peripheral and facial),49 dyspnea,1, 49 asthma,1 exacerbation of asthma,1, 49 dizziness,1 headache,1 migraine headache,71 tachycardia,49 angina,1 palpitations,1 unstable angina,1 myocardial infarction,49 chest pain,1 cerebrovascular accident,49 and hypertension.49
Laboratory analysis of blood and urine before and during latanoprost therapy have not revealed any substantial change in hematologic, urinary, or clinical chemistry values in patients receiving the drug.3, 10, 11, 12
Precautions and Contraindications
Because topical latanoprost therapy can cause irreversible changes in iris pigmentation (i.e., increased brown pigmentation) in some patients,1, 3, 10, 11, 12, 15, 31, 32, 33, 36 especially those with mixed colored irides,3, 10, 11, 12, 15, 31, 32, 33, 36 patients should be informed of the possibility of iris color change.1 The increase in brown pigmentation presumably is due to an increase in the number of melanosomes (pigment granules) within melanocytes and not due to a proliferation of melanocytes.1 While latanoprost therapy can be continued in patients who experience noticeably increased pigmentation in the iris, these patients should be examined regularly.1, 33, 36 Latanoprost therapy also can cause increases in pigmentation of the periorbital tissue (i.e., eyelid) and gradually cause changes in eyelashes and vellus hair in the treated eye.1 Increased pigmentation of the periorbital tissue may be reversible in some patients following discontinuance of latanoprost;1, 72 eyelash changes usually are reversible upon discontinuance of the drug.1 Patients expected to receive latanoprost therapy in only one eye should be informed of the potential for increased brown pigmentation in the iris, periorbital tissue, eyelashes, and vellus hairs in the treated eye and that heterochromia between the eyes could occur.1, 36 Patients also should be advised of the potential for a disparity between eyes in length, thickness, pigmentation, and number of eyelashes or vellus hairs and/or direction of eyelash growth.1
Latanoprost should be used with caution in patients with a history of ocular inflammation (i.e., iritis/uveitis); the drug generally should not be used in patients with active intraocular inflammation because it may exacerbate the inflammation.1, 57 Because macular edema, including cystoid macular edema, has been reported during therapy with latanoprost, the drug should be used with caution in aphakic patients, pseudophakic patients, and patients with risk factors for macular edema.1, 51, 52, 53, 54, 58, 61, 62, 63, 64, 65
Bacterial keratitis has been reported with the use of multiple-dose containers of topical ophthalmic preparations.1 These containers were contaminated inadvertently by patients who, in most cases, had concurrent corneal disease or disruption of the ocular epithelial surface.1 Patients should be informed that improper handling of ophthalmic preparations can result in contamination of the preparation by common bacteria known to cause ocular infections and that they should avoid allowing the tip of the dispensing container to contact the eye or surrounding structures, fingers, or any other surface.1, 91 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.1 Patients receiving latanoprost ophthalmic preparations should be advised to immediately contact their clinician for advice regarding continued use of the ophthalmic preparation if they develop an intercurrent ocular condition (e.g., trauma, infection) or ocular reaction (particularly conjunctivitis and lid reactions) or require ocular surgery.1, 91
Reactivation of herpes simplex keratitis has been reported in patients receiving latanoprost.1 The drug should be used with caution in patients with a history of herpetic keratitis and should be avoided in those with active herpes simplex keratitis since inflammation may be exacerbated.1
Patients who wear contact lenses should be warned to remove their lenses prior to receiving a dose of a topical ophthalmic preparation containing latanoprost.1, 90, 91 Some such preparations (e.g., ophthalmic solutions containing latanoprost alone or in fixed combination with netarsudil) contain benzalkonium chloride, which may be absorbed by some lenses.1, 91 (See Dosage and Administration: Administration.)
When latanoprost is used in fixed combination with netarsudil, cautions, precautions, and contraindications associated with netarsudil should be considered in addition to those associated with latanoprost.91
Latanoprost is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation (e.g., benzalkonium chloride).1, 90
Safety and efficacy of topical ophthalmic latanoprost have not been established in pediatric patients.1, 15, 90, 91
No overall differences in safety or efficacy of topical ophthalmic latanoprost have been observed between geriatric patients and younger adults.1, 10, 11, 12, 90, 91 Results from phase 3 clinical studies indicate that age does not appear to affect intraocular pressure (IOP) response to latanoprost.3, 10, 11, 12
Mutagenicity and Carcinogenicity
Latanoprost was not mutagenic in microbial (Ames), mouse lymphoma, or in mouse micronucleus tests; however, chromosome aberrations were observed in vitro with human lymphocytes.1
No evidence of carcinogenic potential was observed in mice or rats given latanoprost by oral gavage in dosages up to 170 mcg/kg daily (approximately 2800 times the recommended maximum human dose) for 20 or 24 months, respectively.1 In vitro and in vivo studies evaluating unscheduled DNA synthesis in rats receiving latanoprost were negative.1
Pregnancy, Fertility, and Lactation
Latanoprost has been embryocidal in rabbits when given in dosages greater than 15 times the maximum human dose.1 In rabbits given latanoprost dosages 80 times the maximum human dose, approximately 25% of dams had no viable fetuses.1
There are no adequate and well-controlled studies to date evaluating latanoprost in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 90, 91
Reproductive studies in male and female rats receiving latanoprost have not revealed evidence of impaired fertility.1, 15
It is not known whether latanoprost or its metabolites are distributed into milk following topical application to the eye1, 90, 91 or whether the drug has any effects on the breast-fed infant or on milk production.91
Latanoprost ophthalmic solution or emulsion should be used with caution in nursing women.1, 90
The manufacturer of netarsudil and latanoprost fixed-combination ophthalmic solution states that the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for the drugs and any potential adverse effects of the drugs on the breast-fed infant.91
In vitro studies indicate that precipitation occurs when ophthalmic preparations containing thimerosal are admixed with latanoprost ophthalmic solution or emulsion.1, 90, 91 If an ophthalmic solution or emulsion containing latanoprost is administered to a patient who is receiving an ophthalmic preparation that contains thimerosal, an interval of at least 5 minutes should elapse between administration of latanoprost and the other ophthalmic product.1, 90, 91
Limited information is available on the acute toxicity of latanoprost in humans. While no adverse effects were reported following IV infusion of latanoprost doses up to 3 mcg/kg in healthy individuals, IV infusion of latanoprost doses of 5.5-10 mcg/kg has resulted in abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating.1 Because one of the systemic effects of naturally occurring PGF2α is bronchoconstriction, it has been suggested that a similar effect possibly could occur with high-dose systemic administration of latanoprost.6
If topical overdosage of latanoprost ophthalmic solution occurs, treatment should be symptomatic.1 Overdosage following oral ingestion of the commercially available ophthalmic solution is unlikely given the limited amount of latanoprost present in the solution.15, 44
Latanoprost, a synthetic isopropyl ester analog of prostaglandin F2α (PGF2α), is a selective prostanoid agonist.1, 2, 3, 5, 6, 7, 8, 9, 33, 40 Latanoprost is a prodrug of latanoprost acid and has little, if any, pharmacologic activity until hydrolyzed in vivo to latanoprost acid.1, 6, 15, 32, 33 Naturally occurring PGF2α is a potent FP subtype receptor agonist that also has appreciable agonist activity at some other prostanoid receptors including EP and TP subtypes.4, 6, 40 Latanoprost acid is highly specific for and has high affinity for the FP subtype prostanoid receptor and, to a lesser extent, the EP1 subtype prostanoid receptor.1, 2, 3, 5, 6, 7, 8, 9, 10, 33, 40
Latanoprost is a potent ocular hypotensive agent.1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 33, 36 Following topical application to the eye and in vivo conversion to latanoprost acid, the drug reduces both elevated and normal intraocular pressure (IOP) in patients with or without glaucoma.1, 2, 3, 5, 9, 10, 11, 12, 13, 19, 30, 31, 33, 36, 37, 38 In patients with elevated IOP, topical latanoprost can produce mean IOP reductions of about 23-35% from baseline.3, 9, 10, 11, 12, 13, 19, 30, 36, 38 In healthy individuals with normal IOP or patients with normal-pressure (low-tension) glaucoma, the drug can produce IOP reductions averaging 19-25% from baseline.3, 5, 9, 33, 37 In dose-ranging studies evaluating commercially available latanoprost ophthalmic solution, maximum reduction in IOP occurred with a topical latanoprost dosage of 1.5 mcg daily (i.e., 1 drop [30 µL] of latanoprost ophthalmic solution 0.005% once daily).10, 15, 20, 29, 33, 39 Administration of topical latanoprost twice daily does not result in a greater reduction in IOP than administration of the drug once daily and may paradoxically reduce the IOP-lowering effect of the drug.1, 15, 29, 33, 39 In adults with open-angle glaucoma or ocular hypertension, once daily topical administration of latanoprost effectively lowers IOP during the night and day.3, 11, 13, 17, 33 While results from one study indicated that once daily topical administration of latanoprost in the evening reduces mean diurnal IOP to a greater extent than administration in the morning,10 results of other studies have not shown such a difference.44 Any difference in efficacy between morning and evening administration may reflect the time interval between the latanoprost dose and IOP measurement rather than a difference in effectiveness between morning and evening administration.10, 15, 38, 44 The IOP response to latanoprost does not appear to be affected by age, gender, ethnicity, baseline IOP, diagnosis, or previous treatment with β-adrenergic receptor blocking agents (e.g., timolol).3, 10, 11, 12, 33, 36 Results of one study suggested that the response to latanoprost was better in patients with hazel eyes than in those with blue-green-grey eyes;12 however, iris color did not affect IOP response to the drug in two other studies.10, 11, 44
The exact mechanism by which latanoprost reduces IOP has not been fully elucidated.1, 2, 3, 5, 7, 9, 33 Pharmacodynamic studies suggest that increased outflow of aqueous humor, specifically increased uveoscleral outflow, is the principal effect.1, 2, 3, 5, 6, 7, 9, 31, 32, 33 In one study, uveoscleral outflow increased from a baseline rate of 0.39 µL/minute to 0.87 µL/minute following topical application of latanoprost 0.006% twice daily for 8 days.5, 33 In the normal eye, outflow of aqueous humor occurs principally through the trabecular meshwork to the canal of Schlemm and, to a lesser extent, by uveoscleral outflow through the ciliary muscle, suprachoroidal space, and the sclera.33, 34 While aqueous humor leaving the eye through the trabecular meshwork and Schlemm's canal is opposed by a pressure gradient of about 10 mm Hg (the episcleral venous pressure), uveoscleral outflow drains against an intraorbital pressure of essentially 0 mm Hg.7, 11, 13 The more favorable pressure gradient associated with uveoscleral outflow may account for the substantial ocular hypotensive effect associated with topical PGF2α and its analogs.7, 11, 15, 44 Because uveoscleral outflow is independent of the postural effects of episcleral venous pressure, PGF2α and its analogs lower IOP in patients who are supine to a similar extent as in patients who are sitting.13 Although the biochemical or cellular mechanism by which PGF2α and its analogs increase uveoscleral outflow has not been studied in humans, studies in nonhuman primates suggest that outflow is increased by relaxation of the ciliary muscle or alterations in its interstitial matrix, resulting in greater pressure-dependent flow through the uvea.3, 5, 7, 8, 13, 31 In vitro studies in human ciliary muscle cells indicate that PGF2 a and its analogs increase prometalloproteinases and metalloproteinases, resulting in degradation or remodeling of the ciliary muscle extracellular matrix.42, 43, 44 However, prostaglandins modulate and modify many cellular functions and other mechanisms of action may contribute to IOP-lowering activity.3, 13 Latanoprost acid is highly specific for and has a high affinity for the FP subtype prostanoid receptor,2, 6, 10, 33, 40 and it has been suggested that uveoscleral outflow may be mediated by the FP receptor.2, 3, 6, 15, 44 Latanoprost reduces IOP without affecting pupillary size or accommodation.3, 10, 11, 12, 33
Glaucoma generally results from impaired outflow of aqueous humor rather than excessive formation.11, 23, 24, 25, 26 Unlike some other topical ocular hypotensive agents, including β-adrenergic blocking agents (e.g., betaxolol, levobunolol, timolol) and carbonic anhydrase inhibitors (brinzolamide, dorzolamide), latanoprost does not reduce aqueous humor formation.2, 5, 9, 12, 31 Because avascular ocular structures depend on aqueous humor flow for metabolic exchanges, long-term reduction in aqueous humor formation may have deleterious effects.11 Because latanoprost lowers IOP by increasing outflow, effects associated with long-term reduction in aqueous humor formation are avoided; however, the long-term effect of diverting flow through the ciliary muscle and alteration of the ciliary muscle extracellular matrix have not been determined.2, 11, 44
While studies in animals indicate that naturally occurring PGF2α can affect the permeability of the blood-aqueous barrier and cause vascular effects and changes in blood flow in the eye, studies using latanoprost in patients with open-angle glaucoma or ocular hypertension indicate that this analog has no effect on capillary permeability in ocular tissues or permeability of the blood-aqueous barrier, has no adverse effects on ocular blood flow, and generally does not cause ocular irritation.2, 6, 9, 10, 11, 12, 30, 31, 33, 38
Topical administration of latanoprost has been associated with minimal systemic effects to date.1, 6, 10, 11, 12, 33, 44 Naturally occurring PGF2α stimulates the contraction of uterine and bronchial smooth muscle and produces vasoconstriction in some vessels.35 Because naturally occurring PGF2α can cause bronchoconstriction, it has been suggested that a similar effect possibly could occur with high-dose systemic administration of latanoprost.6 However, studies evaluating the systemic effects of latanoprost in various animals indicate that systemically administered latanoprost has little, if any, effect on cardiovascular and pulmonary systems.6, 33 Results of a study in patients with asthma (no previous exposure to inhaled corticosteroids) indicate that latanoprost administration is not associated with changes in morning and evening peak expiratory flow, daytime or nocturnal asthma symptoms, or use of asthma medications.67 In anesthetized cynomolgus monkeys, administration of latanoprost 0.6 mcg/kg IV had no clinically important effect on arterial blood pressure, cardiac output, heart rate, stroke volume, cardiac work, or coronary blood flow.6 In addition, IV latanoprost was not associated with clinically important effects on respiration rate in monkeys breathing normally or on the intrathoracic inspiratory-expiratory pressure difference and had no effect on blood flow to the eye, brain, stomach, small intestine, colon, liver, kidneys, urogenital organs, or bronchial arteries.6, 33
Latanoprost is a prodrug of latanoprost acid and has little, if any, pharmacologic activity until hydrolyzed in vivo to latanoprost acid.1, 6, 15
The extent of ocular and systemic absorption of latanoprost following topical application to the eye has not been fully elucidated.6, 14, 15, 16 Studies using radiolabeled latanoprost indicate that about 1% of a topical dose of the drug penetrates the human eye.15 The remaining portion is absorbed into systemic circulation through blood vessels in the conjunctiva and mucous membranes of the nose, pharynx, esophagus, and GI tract.6, 15 Drug absorbed through the cornea is rapidly and completely hydrolyzed to latanoprost acid by esterases present in the cornea.1, 6, 14, 15, 16, 18 Measurable concentrations of biologically active latanoprost acid are present in aqueous humor during the first 4 hours after topical application of latanoprost to the eye, with peak concentrations reached within 2 hours following a topical dose.1, 15 Following topical application to the eye of 1 drop (30 µL) of a 0.005% solution (1.5 mcg) of latanoprost 0.5-24 hours prior to surgery in a limited number of patients undergoing cataract extraction, aqueous humor concentrations of latanoprost acid averaged 5.7 ng/mL at 30 minutes, 18.7 ng/mL at 1 hour, 32.6 ng/mL at 2 hours, 29 ng/mL at 4 hours, and less than 0.2 ng/mL at 24 hours after the dose.15
A reduction in intraocular pressure (IOP) generally occurs within 3-4 hours after topical application of latanoprost, peaks within 8-12 hours, and persists for up to 24 hours or longer.1, 10, 11, 12, 13, 15, 17 In patients who have received long-term therapy with latanoprost ophthalmic solution (i.e., 6 months), pharmacologic effects may persist for at least 14 days after the drug is discontinued.15
Although some systemic absorption of latanoprost occurs following topical application of the drug to the eyes, latanoprost appears to have a low potential for causing systemic effects.1, 6, 10, 11, 12 Systemically absorbed latanoprost is almost completely hydrolyzed to latanoprost acid by esterases present in the plasma.6, 15 In patients receiving a single 3-mcg dose of latanoprost ophthalmic solution in phase 2 studies, approximately 45% of the dose was present in systemic circulation as biologically active latanoprost acid.15 Measurable concentrations of latanoprost acid are present in plasma only during the first hour following topical application to the eye.1 In healthy males who received 1 drop (30 µL) of a 0.005% solution (1.5 mcg) of radiolabeled latanoprost in each eye, peak plasma concentrations of latanoprost acid occurred within 5-15 minutes and were 53 pg/mL.15 In a limited number of patients receiving long-term therapy (i.e., minimum of 1 year) with usual doses of latanoprost ophthalmic solution (1.5 mcg of latanoprost in each eye once daily), peak plasma concentrations of latanoprost acid were 32-67 pg/mL in 40% of these patients but were less than 30 pg/mL (the minimum level of detection) in 60% of patients; plasma concentrations of latanoprost were below the level of detection (30 pg/mL) in all patients.15
The volume of distribution of latanoprost acid in humans following topical or IV administration is 0.36 or 0.16 L/kg, respectively.15 Latanoprost is about 90% protein bound immediately after IV administration; protein binding reportedly decreases to about 60% within 2 hours.33
It is not known whether latanoprost or latanoprost acid is distributed into human milk.1
Latanoprost is rapidly hydrolyzed to latanoprost acid by esterases in the cornea and plasma.1, 15, 16, 33 The elimination half-life of latanoprost acid from aqueous humor has been estimated to be 3 hours.15 Following IV or topical administration of latanoprost, plasma concentrations of latanoprost acid decline rapidly with a plasma elimination half-life of 17 minutes.15 Systemic clearance following topical or IV administration averages 7 mL/minute per kg.1
Although naturally occurring prostaglandins are metabolized in the lungs by 15-prostaglandin dehydrogenase (15-PGDH), latanoprost acid is a poor substrate for 15-PGDH and its metabolism does not occur via this enzyme.6, 15, 16, 33 The double bond between carbon 13 and 14 and the phenyl ring on the omega chain of latanoprost may account for the poor binding between latanoprost acid and 15-PGDH.15 Following topical application to the eye, latanoprost absorbed through the cornea is hydrolyzed to latanoprost acid and does not appear to undergo additional metabolism in ocular tissues.6, 16, 33 Systemically absorbed latanoprost acid is metabolized in the liver by fatty acid β-oxidation to the 1,2-dinor and 1,2,3,4-tetranor metabolites.1, 15 These metabolites are excreted principally in the urine; however, biliary excretion may also occur since radioactivity has been detected in feces following IV administration of radiolabeled latanoprost.1, 6, 15 Unchanged latanoprost or latanoprost acid generally are not recovered in urine or feces.15 Following IV or topical administration of radiolabeled latanoprost, 98 or 88% of the dose was eliminated in urine.1, 15 In these studies, IV and topical administration was associated with quantitative recovery of total radioactivity, indicating that no drug or drug related compounds remained in the body.15
Latanoprost, a synthetic analog of naturally occurring prostaglandin F2α (PGF2α), is an ocular hypotensive agent.1, 2, 3, 32, 33 The drug differs structurally from PGF2α by the presence of an isopropyl group at the carboxylic acid terminal, the presence of a saturated double-bond between carbon 13 and 14, and substitution of a phenyl ring for part of the omega chain.1, 2, 3, 15, 30 Esterification of the carboxylic acid terminal of PGF2α increases lipophilicity resulting in better corneal penetration following topical administration, and the phenyl group improves ocular tolerability.2, 3, 14, 33 Latanoprost is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to latanoprost acid.1, 6, 15, 32, 33 Latanoprost, also known as PhXA41, is one of several 17-phenyl substituted isopropyl ester analogs of PGF2α that have been investigated for use as ocular hypotensive agents.2, 3, 18 While initial studies focused on PhXA34, an equimolar mixture of 15 R and 15 S epimers of a 17-phenyl substituted PGF2α analog, subsequent studies focused on latanoprost which is the 15 R epimer of PhXA34.2, 3, 33 Because the 15 S epimer has about 10% of the activity of the 15 R epimer, latanoprost is about twice as potent as PhXA34.2, 3
Latanoprost occurs as a colorless to slightly yellow oil.1 Latanoprost is freely soluble in alcohol and practically insoluble in water,1 having a solubility of 200 mg/mL in alcohol and 50 mcg/mL in water at 25°C.15 The estimated pKa of the drug is 4.88.15
Commercially available latanoprost ophthalmic solution is a clear, colorless, isotonic, buffered, aqueous solution of the drug that contains benzalkonium chloride as a preservative.1 The solution has a pH of approximately 6.7.1, 15
Commercially available latanoprost ophthalmic emulsion is an off-white to pale yellow, translucent, isotonic, sterile, buffered, aqueous emulsion of the drug that contains potassium sorbate as a preservative.90 The emulsion has a pH of approximately 7.90
Commercially available netarsudil and latanoprost fixed-combination ophthalmic solution is an isotonic, buffered, aqueous solution of the drugs that contains benzalkonium chloride as a preservative.91 The solution has a pH of approximately 5.91
Unopened bottles of latanoprost ophthalmic solution should be refrigerated at 2-8°C and protected from light.1, 15 During shipment to the patient, the bottle may be maintained at temperatures up to 40°C for a period not exceeding 8 days.1 The bottle in use may be stored at room temperature for up to 6 weeks but should not be exposed to temperatures exceeding 25°C.1
Latanoprost ophthalmic emulsion should be stored at 2-25°C and protected from light.90 During shipment to the patient, the bottle may be maintained at temperatures up to 40°C for a period not exceeding 8 days.90 Opened bottles may be used until the manufacturer's labeled expiration date and then discarded.90
Netarsudil and latanoprost fixed-combination ophthalmic solution should be refrigerated at 2-8°C and protected from light.91 During shipment, the bottle may be maintained at temperatures up to 40°C for a period not exceeding 14 days.91 Opened bottles may be used until the manufacturer's labeled expiration date and then discarded.91
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Emulsion | 0.005% | Xelpros® | Sun |
Solution | 0.005%* | Latanoprost Ophthalmic Solution | ||
Xalatan® | Pfizer |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Solution | 0.005% with Netarsudil Mesylate 0.02% (of netarsudil) | Rocklatan® | Aerie |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions October 19, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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