la-TAN-oh-prost

Alternative Names:

Dosage Forms in the United States
Legal Status Rx Dosing Adjustment None
Controlled Substance No NNMC Formulary Formulary but not Xelpros or Iyuzeh
Age Limits Yes Maximum Dose Yes
Recent Major Changes No Boxed Warning No
Pharmacologic Category Route
  • Ophthalmic
Structure Not Available

INDICATION SPECIFIC DOSING

  • Open-angle glaucoma

    • Solution, Ophthalmic; 0.005%: Xalatan, Xelpros, Iyuzeh, or Generic (2.5 mL, 30 pouch of 0.2 mL)
      • Adults: One drop in the affected eye(s) once daily in the evening.

DOSING ADJUSTMENT

  • Hepatic Impairment:

    • Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Latanoprost should be used with caution in patients with hepatic impairment; data are lacking in these patients.

  • Renal Impairment:

    • Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Latanoprost should be used with caution in patients with renal impairment; data are lacking in these patients. For intermittent hemodialysis, no dosage adjustment is needed.

MAXIMUM DOSAGE

  • Adults: 1 drop/day per affected eye.
  • Geriatric: 1 drop/day per affected eye
  • Adolescents: Safety and efficacy have not been established.
  • Children: Safety and efficacy have not been established.
  • Infants: Safety and efficacy have not been established.
  • Neonates: Safety and efficacy have not been established.

SPECIAL POPULATIONS

    Pediatric

    • Safety and effectiveness in pediatric patients have not been established.

    Pregnancy

    • There are no adequate and well-controlled studies of XALATAN administration in pregnant women to inform drug-associated risks. In animal reproduction studies, intravenous (IV) administration of latanoprost to pregnant rabbits and rats throughout the period of organogenesis produced malformations, embryofetal lethality and spontaneous abortion at clinically relevant doses. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20% of clinically recognized pregnancies.
    • Animal Data: Embryofetal studies were conducted in pregnant rabbits administered latanoprost daily by IV injection on gestation days 6 through 18, to target the period of organogenesis. A no observed adverse effect level (NOAEL) was not established for rabbit developmental toxicity. Post-implantation loss due to late resorption was shown as doses ≥0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [RHOD], on a mg/m basis, assuming 100% absorption). Spina bifida and abortion occurred at 5 mcg/kg/day (equivalent to 32 times the maximum RHOD). Total litter loss due to early resorption was observed at doses ≥50 mcg/kg/day (324 times the maximum RHOD). Transient signs of maternal toxicity were observed after IV dosing (increased breathing, muscle tremors, slight motor incoordination) at 300 mcg/kg/day (1946 times the maximum RHOD). No maternal toxicity was observed at doses up to 50 mcg/kg/day.
      Embryofetal studies were conducted in pregnant rats administered latanoprost daily by IV injection on gestation days 6 through 15, to target the period of organogenesis. A NOAEL for rat developmental toxicity was not established. Cleft palate was observed at 1 mcg/kg (equivalent to 3.2 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption). Brain porencephalic cyst(s) were observed ≥50 mcg/kg (162 times the maximum RHOD). Skeletal anomalies were observed at 250 mcg/kg (811 times the maximum RHOD). No maternal toxicity was detectable at 250 mcg/kg/day. Prenatal and postnatal development was assessed in rats. Pregnant rats were administered latanoprost daily by IV injection from gestation day 15, through delivery, until weaning (lactation Day 21). No adverse effects on rat offspring were observed at doses up to 10 mcg/kg/day (32 times the maximum RHOD, on a mg/m basis, assuming 100% absorption). At 100 mcg/kg/day (324 times the maximum RHOD), maternal deaths and pup mortality occurred.

    Breast Feeding

    • It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Latanoprost is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Latanoprost and any potential adverse effects on the breastfed child from Latanoprost.

    Geriatric

    • No overall differences in safety or effectiveness have been observed between elderly and younger patients.

ADMINISTRATION

  • Solution

    The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one dose is missed, treatment should continue with the next dose as normal. The dosage of Latanoprost should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including Latanoprost is not recommended.
    It has been shown that administration of these prostaglandin drug products more than once daily may decrease the IOP lowering effect or cause paradoxical elevations in IOP. Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours.
    Latanoprost may be used concomitantly with other topical ophthalmic drug products to lower IOP. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with Latanoprost. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. Contact lenses should be removed prior to the administration of Latanoprost, and may be reinserted 15 minutes after administration.

MONITORING PARAMETERS

    • Intraocular pressure
    • Ocular pigmentation changes

CONTRAINDICATIONS

  • Solution

    • Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product.

WARNINGS AND PRECAUTIONS

  • Pigmentation

    • Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris pigmentation likely to be permanent

  • Eyelash Changes

    • Gradual change to eyelashes including increased length, thickness and number oflashes. Usually reversible.

ADVERSE REACTIONS

  • Solution

    • Most common adverse reactions (5-15%) from clinical trials are blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate keratitis.

  • Postmarketing Adverse Events

  • Drug Recall

INTERACTIONS

  • Eye drops containing thimerosal: In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with Latanoprost. If such drugs are used, they should be administered at least five (5) minutes apart.
  • Prostaglandin analogs: The combined use of two or more prostaglandins, or prostaglandin analogs including Latanoprost is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the IOP lowering effect or cause paradoxical elevations in IOP.

STORAGE AND HANDLING

  • XALATAN is a clear, isotonic, buffered, preserved colorless solution of latanoprost 50 mcg/mL (0.005%). It is supplied as a 2.5 mL solution in a 5 mL clear low density polyethylene bottle with a clear polyethylene dropper tip, a turquoise high density polyethylene screw cap, and a tamper-evident clear low density polyethylene overcap.
    Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2°C to 8°C (36°F to 46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks.
  • XELPROS (latanoprost ophthalmic emulsion) is supplied as an off-white to pale yellow, translucent, isotonic, sterile, buffered emulsion of latanoprost 0.005% (50 mcg/mL). It is supplied as a 2.5 mL emulsion filled in a 5-mL clear low density polyethylene bottle with a clear low density polyethylene dropper tip, and a turquoise high density polyethylene pilfer-proof cap. Each mL contains 50 mcg of latanoprost.
    Storage: Protect from light. Store at 2°C to 25°C (36°F to 77°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. After opening, XELPROS can be used until the expiration date stamped on bottle and then discarded.
  • IYUZEH (latanoprost ophthalmic solution) is an opalescent, isotonic, white to slightly yellow solution of latanoprost 50 mcg/mL (0.005%) practically free from foreign particles. It is supplied as a sterile solution in translucent low-density polyethylene single-dose container packaged in foil pouches (5 single-dose containers per pouch).
    Storage: Store at 15°C to 25°C (59°F to 77°F). Store in the original pouch. After the pouch is opened, the single-dose containers may be stored in the opened foil pouch for up to 30 days at room temperature 15°C to 25°C (59°F to 77°F). Patient should be advised to write down the date the foil pouch is opened in the space provided on the pouch. Discard any unused containers 30 days after first opening the pouch.

DESCRIPTION

  • Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C H O and its chemical structure is shown above.
    Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically insoluble in water.
  • XALATAN (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of XALATAN contains 50 mcg of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. One drop contains approximately 1.5 mcg of latanoprost.
  • XELPROS (latanoprost ophthalmic emulsion) 0.005% is a sterile, isotonic, buffered aqueous emulsion of latanoprost with a pH approximately 7.0 and an osmolality of approximately 375mOsmol/kg. Each mL of XELPROS contains 50 micrograms of latanoprost. Potassium sorbate 0.47% is added as a preservative. The inactive ingredients are: castor oil, sodium borate, boric acid, propylene glycol, edetate disodium, polyoxyl 15 hydroxystearate, sodium hydroxide, hydrochloric acid, and water for injection. One drop contains approximately 1.5 mcg of latanoprost.
  • IYUZEH (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, aqueous solution of latanoprost with a pH of approximately 7 and an osmolality of approximately 280 mOsmol/kg. Each mL of IYUZEH contains 50 mcg of latanoprost. The inactive ingredients are: polyoxyl 40 hydrogenated castor oil, sorbitol, carbomer 974P, polyethylene glycol 4000, disodium edetate, sodium hydroxide (for pH-adjustment) and water for injections. One drop contains approximately 1.5 mcg of latanoprost. IYUZEH does not contain a preservative.

PHARMACOLOGY

  • Drug Ingredients

    • Active Ingredient
    • LatanoprostUNII: (UNII: 6Z5B6HVF6O, 0.05 mg in 1 mL)
    Inactive Ingredients
    • XALATAN
      • Benzalkonium Chloride: (UNII: F5UM2KM3W7)
      • Sodium Chloride: (UNII: 451W47IQ8X)
      • Sodium Phosphate, Dibasic, Anhydrous: (UNII: 22ADO53M6F)
      • WATER: (UNII: 059QF0KO0R)
    • XELPROS
      • Potassium Sorbate: (UNII: 1VPU26JZZ4, 4.70 mg in 1 mL)
      • Boric Acid: (UNII: R57Z HV85D4, 3.00 mg in 1 mL)
      • Edetate Disodium: (UNII: 7FLD91C86K, 3.00 mg in 1 mL)
      • Castor Oil: (UNII: D5340Y2I9G, 1.5 mg in 1 mL)
      • Polyoxyl 15 Hydroxystearate: (UNII: 71YMM1X75O, 2.5 mg in 1 mL)
      • Propylene Glycol: (UNII: 6DC9Q167V3, 15 mg in 1 mL)
      • Sodium Borate: (UNII: 91MBZ8H3QO, 1.1 mg in 1 mL)
      • Hydrochloric Acid: (UNII: QTT17582CB)
      • Sodium Hydroxide: (UNII: 55X04QC32I)
      • WATER: (UNII: 059QF0KO0R)
    • IYUZEH
      • Sorbitol: (UNII: 506T60A25R)
      • Carbomer Homopolymer Type B (Allyl Pentaerythritol Crosslinked: (UNII: HHT01ZNK31)
      • Polyoxyl 40 Hydrogenated Castor Oil: (UNII: 7YC686GQ8F)
      • Polyethylene Glycol 4000: (UNII: 4R4HFI6D95)
      • Edetate Disodium: (UNII: 7FLD91C86K)
      • Sodium Hydroxide: (UNII: 55X04QC32I)
      • WATER: (UNII: 059QF0KO0R)

  • Mechanism Of Action

    • Reduction of intraocular pressure (IOP):
      • Latanoprost is a prostaglandin F analogue that is believed to reduce the IOP by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

  • Pharmacokinetics

    • Absorption
      • Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active
    • Distribution
      • The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the first hour after local administration. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.
    • Metabolism
      • Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
    • Excretion
      • The elimination of the acid of latanoprost from human plasma is rapid (t½ = 17 min) after both IV and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose are recovered in the urine after topical and IV dosing, respectively.

  • Pharmacodynamics

    • Reduction of intraocular pressure (IOP)
      • Reduction of the IOP in man starts about 3-4 hours after administration and maximum effect is reached after 8-12 hours. IOP reduction is present for at least 24 hours.

CLINICAL STUDIES

  • Elevated Baseline IOP: Patients with mean baseline IOP of 24-25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP reduction with Latanoprost 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.
  • Progression of Increased Iris Pigmentation: A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of Latanoprost once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of the 380 patients who continued in the extension phase. Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the 5 years of the study. Observation of increased iris pigmentation did not affect the incidence, nature, or severity of adverse events (other than increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development of increased iris pigmentation during the study.

TOXICOLOGY

  • Overdosage

    • IV infusion of up to 3 mcg/kg of latanoprost in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment with Latanoprost and no adverse reactions were observed. IV dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating. If overdosage with Latanoprost occurs, treatment should be symptomatic.

  • Carcinogenesis and Mutagenesis and Impairment of Fertility

    • Carcinogenesis
      • Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.
    • Mutagenesis
      • Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.
    • Impairment of Fertility
      • Latanoprost has not been found to have any effect on male or female fertility in rat studies at IV doses up to 250 mcg/kg/day (811 times the maximum RHOD, on a mg/m2 basis, assuming 100% absorption)

PATIENT EDUCATION

  • XALATAN

      • Potential for Pigmentation
    • Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of XALATAN
      • Potential for Eyelash Changes
    • Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with XALATAN. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.
      • Handling the Container
    • Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions
      • When to Seek Physician Advice
    • Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of the multiple-dose container
      • Contact Lens Use
    • Advise patients that XALATAN contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of XALATAN.
      • Use with Other Ophthalmic Drugs
    • Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.
      • If a Dose is Missed
    • Advise patients that if one dose is missed, treatment should continue with the next dose as normal.

  • XELPROS

      • Potential for Pigmentation
    • Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Patients should also be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of XELPROS.
      • Potential for Eyelash Changes
    • Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with latanoprost ophthalmic emulsion. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.
      • Handling the Container
    • Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated emulsions
      • When to Seek Physician Advice
    • Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of the multiple-dose container.
      • Contact Lens Use
    • Advise patients that contact lenses should be removed prior to administration of the emulsion. Lenses may be reinserted 15 minutes following administration of XELPROS.
      • Use with Other Ophthalmic Drugs
    • Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.
      • If a Dose is Missed
    • Advise patients that if one dose is missed, treatment should continue with the next dose as normal.

  • IYUZEH

      • Potential for Pigmentation
    • Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of IYUZEH.
      • Potential for Eyelash Changes
    • Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with latanoprost ophthalmic solution. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.
      • Handling the Container
    • Advise patients that IYUZEH is a sterile solution that does not contain a preservative. The drops are supplied in single-dose container. The solution from one individual container is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual container is opened, the remaining contents should be discarded immediately after administration. Open a new single-dose container every time you use IYUZEH.
      • When to Seek Physician Advice
    • Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician’s advice concerning the continued use of IYUZEH.
      • Contact Lens Use
    • Advise patients that contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of IYUZEH.
      • Use with Other Ophthalmic Drugs
    • Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.
      • If a Dose is Missed
    • Advise patients that if one dose is missed, treatment should continue with the next dose as normal.

REFERENCE