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LATANOPROST AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bimatoprost, latanoprost, tafluprost, and travoprost are prostaglandin analogs and selective FP prostanoid receptor agonist. Latanoprost, tafluprost, and travoprost reduce intraocular pressure (IOP) by increasing uveoscleral outflow. Bimatoprost lowers IOP by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral drainage systems. The exact mechanism of action for bimatoprost in stimulating eyelash growth is unknown; it may work by increasing the duration and the percentage of hairs in the anagen or growth phase.

Specific Substances

    A) BIMATOPROST
    1) AGN-192024
    2) Bimatoprostum
    3) CAS 155206-00-1
    LATANOPROST
    1) Latanoprosti
    2) PhXA41
    3) XA-41
    4) CAS 130209-82-4
    TAFLUPROST
    1) AFP-168
    2) DE-085
    3) MK-2452
    4) Tafluprostum
    5) CAS 209860-87-7
    TRAVOPROST
    1) AL-6221
    2) Travoprosti
    3) Travoprostum
    4) CAS 157283-68-6
    UNOPROSTONE ISOPROPYL
    1) Isopropyl Lunoprostone
    2) Isopropyl Unoprostone
    3) UF-021
    4) Unoprostona de isopropilo
    5) CAS 120373-36-6 (unoprostone)
    6) CAS 120373-24-2 (unoprostone isopropyl)

    1.2.1) MOLECULAR FORMULA
    1) LATANOPROST: C26H40O5
    2) TAFLUPROST: C25H34F2O5
    3) TRAVOPROST: C26H35F3O6

Available Forms Sources

    A) FORMS
    1) Bimatoprost is available as 0.01% and 0.03% ophthalmic solutions (Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info LATISSE(R) ophthalmic solution, 2009).
    2) COMBINATION PRODUCTS: Bimatoprost 0.3 mg/mL/timolol 5 mg/mL (as 6.8 mg of timolol maleate) and travoprost 40 mcg/mL/timolol 5 mg/mL (as timolol maleate) combinations are available as ophthalmic solution (Prod Info GANFORT ophthalmic solution, 2011; Prod Info DuoTrav ophthalmic solution, 2012).
    3) Latanoprost is available as 0.005% (50 mcg/mL) ophthalmic solution (Prod Info Xalatan(R) ophthalmic solution, 2009).
    4) Tafluprost is available as 0.015 mg/mL ophthalmic solution. Each single-use container has 0.3 mL solution with 0.0045 mg tafluprost (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    5) Travoprost is available as 0.004% (0.04 mg/mL) ophthalmic solution (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    6) Unoprostone is no longer available in the United States.
    B) USES
    1) Bimatoprost, latanoprost, tafluprost, and travoprost are indicated for the reduction of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info TRAVATAN(R) ophthalmic solution, 2011; Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info Xalatan(R) ophthalmic solution, 2009). Bimatoprost 0.03% ophthalmic solution (Latisse(R)) is also indicated for the treatment of hypotrichosis of the eyelashes (Prod Info LATISSE(R) ophthalmic solution, 2009).
    2) COMBINATION PRODUCTS: Bimatoprost or travoprost in combination with timolol are used to reduce intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues (Prod Info DuoTrav ophthalmic solution, 2012; Prod Info GANFORT ophthalmic solution, 2011).
    3) Unoprostone was used for the treatment of glaucoma and ocular hypertension (Prod Info RESCULA(R) ophthalmic solution, 2001). Unoprostone is no longer available in the United States.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Bimatoprost, latanoprost, tafluprost, travoprost, bimatoprost/timolol and travoprost/timolol are indicated for the reduction of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma. Bimatoprost 0.03% ophthalmic solution (Latisse(R)) is also indicated for the treatment of hypotrichosis of the eyelashes. Refer to BETA-BLOCKING AGENTS management for more information about timolol.
    B) PHARMACOLOGY: These agents are prostaglandin analogs and selective FP prostanoid receptor agonist. Latanoprost, tafluprost, and travoprost reduce intraocular pressure (IOP) by increasing uveoscleral outflow. Bimatoprost lowers IOP by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral drainage systems. The exact mechanism of action for bimatoprost in stimulating eyelash growth is unknown; it may work by increasing the duration and the percentage of hairs in the anagen or growth phase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following ocular effects have been reported in patients using the ophthalmic products: Conjunctival hyperemia, iris pigmentation, abnormal vision, blurred vision, allergic conjunctivitis, eye discharge, tearing, photophobia, ocular dryness, visual disturbance, burning, eye pain, blepharitis, cataracts, superficial punctate keratitis, eyelid erythema, pruritus, conjunctival edema, and macular edema. Punctate epithelial keratopathy, ocular hypotony, choroidal effusions, and dendritiform epitheliopathy were reported with latanoprost. OTHER EFFECTS: Bimatoprost: Elevated liver enzymes, headache, asthenia. Latanoprost: Chest pain and/or angina, muscle, joint and back pain, dizziness, headache. Travoprost: Hypertension, chest pain and/or angina, bradycardia, headache. Tafluprost: headache.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The risk of toxicity from inadvertent ingestion is low because the amount contained in the bottles of ophthalmic solution is small. LATANOPROST: There are no reports of ingestion or ocular administration of large doses of latanoprost in humans. No adverse effects were reported after intravenous infusion of up to 3 mcg/kg (produced greater than 200 times therapeutic plasma level) in healthy volunteers. Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating. However, latanoprost is only available as ophthalmic solutions.
    0.2.20) REPRODUCTIVE
    A) Bimatoprost, latanoprost, tafluprost, and travoprost are classified as FDA pregnancy category C. The use of these drugs has not been studied in pregnant woman. In animal studies, skeletal malformations have been observed with tafluprost and travoprost. Increased incidences of fetal death and reduced birth weight have been observed with bimatoprost, latanoprost, tafluprost, and travoprost. It is not known whether any of these drugs or their metabolites are excreted in human milk. However, bimatoprost, tafluprost, and travoprost were excreted in breast milk in animal studies. Bimatoprost, latanoprost, tafluprost, and travoprost did not impair fertility in animal studies. However, an increase in post-implantation losses was noted with tafluprost and travoprost, and travoprost caused a reduction in the mean number of corpora lutea.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers of bimatoprost, latanoprost, tafluprost, and travoprost do not report any carcinogenic potentials in humans.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose. Perform an ophthalmologic exam (including visual acuity and slit lamp) in any patient with persistent eye irritation.
    C) DECONTAMINATION
    1) PREHOSPITAL: Although these agents have not been associated with oral toxicity, inadvertent ingestion of the ophthalmic solution may occur. Due to limited expected toxicity, gastrointestinal decontamination is not routinely recommended. Since the amount of active ingredient available in ophthalmic solutions are very small, acute overdose in adults is unlikely to result in clinically significant adverse events. OCULAR: Flush eyes with copious amounts of water; if symptoms persist an eye exam may be indicated.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary. OCULAR: Flush eyes with copious amounts of water; if symptoms persist an eye exam may be indicated.
    D) AIRWAY MANAGEMENT
    1) Should not be required in these cases.
    E) ANTIDOTE
    1) None.
    F) HYPERTENSIVE EPISODE
    1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside or phentolamine are preferred, with nitroglycerin or labetalol as alternatives.
    G) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is not recommended.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Any patient with symptoms or deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or for whom diagnosis is unclear. Consult an ophthalmologist for managing a patient with severe eye irritation.
    I) PITFALLS
    1) If significant toxicity develops, the diagnosis should be reconsidered. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) BIMATOPROST: Tmax: 10 min; bioavailability: low; protein binding: about 12%; Vd: 0.67 L/kg. Metabolism: Liver, extent unknown; oxidation, N-deethylation, glucuronidation to a variety of metabolites, extent unknown. Excretion: Up to 67% of the bimatoprost dose was eliminated in the urine. Elimination half-life: 45 minutes: LATANOPROST: Tmax: 2 hours; absorbed through the cornea as the isopropyl ester prodrug; Vd: 0.16 L/kg. Metabolism: Latanoprost is rapidly hydrolyzed following ocular administration. Excretion: About 88% to 98% recovered in the urine after topical and IV dosing. Elimination half-life: about 10 minutes. TAFLUPROST: Tmax: 10 min. Metabolism: Hydrolyzed in the eye to tafluprost acid, the biologically active metabolite, which is then metabolized by fatty acid beta-oxidation and phase II conjugation. TRAVOPROST: Tmax: within 30 min. Metabolism: Hydrolyzed by esterases in the cornea to its biologically active free acid form.

Range Of Toxicity

    A) TOXICITY: No toxic ingestions have been reported. The risk of toxicity from inadvertent ingestion is low because the amount contained in the bottles of ophthalmic solution is small. LATANOPROST: Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating. No adverse effects were reported after intravenous infusion of up to 3 mcg/kg (produced greater than 200 times therapeutic plasma level) in healthy volunteers.
    B) THERAPEUTIC DOSES: ADULTS: ALL AGENTS: 1 drop in affected eye(s) once daily in the evening. CHILDREN: LATISSE(R): In a 16-week double-masked, randomized, vehicle-controlled study, bimatoprost ophthalmic solution (0.03%) was administered to pediatric patients (age range, 5 to 17 years) with alopecia areata (n=15) or after chemotherapy (n=16), and to adolescents (age range, 15 to 17 years) with hypotrichosis (n=40). There were no new safety issues in these patients. ALL OTHER AGENTS: Safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Bimatoprost, latanoprost, tafluprost, travoprost, bimatoprost/timolol and travoprost/timolol are indicated for the reduction of elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma. Bimatoprost 0.03% ophthalmic solution (Latisse(R)) is also indicated for the treatment of hypotrichosis of the eyelashes. Refer to BETA-BLOCKING AGENTS management for more information about timolol.
    B) PHARMACOLOGY: These agents are prostaglandin analogs and selective FP prostanoid receptor agonist. Latanoprost, tafluprost, and travoprost reduce intraocular pressure (IOP) by increasing uveoscleral outflow. Bimatoprost lowers IOP by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral drainage systems. The exact mechanism of action for bimatoprost in stimulating eyelash growth is unknown; it may work by increasing the duration and the percentage of hairs in the anagen or growth phase.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following ocular effects have been reported in patients using the ophthalmic products: Conjunctival hyperemia, iris pigmentation, abnormal vision, blurred vision, allergic conjunctivitis, eye discharge, tearing, photophobia, ocular dryness, visual disturbance, burning, eye pain, blepharitis, cataracts, superficial punctate keratitis, eyelid erythema, pruritus, conjunctival edema, and macular edema. Punctate epithelial keratopathy, ocular hypotony, choroidal effusions, and dendritiform epitheliopathy were reported with latanoprost. OTHER EFFECTS: Bimatoprost: Elevated liver enzymes, headache, asthenia. Latanoprost: Chest pain and/or angina, muscle, joint and back pain, dizziness, headache. Travoprost: Hypertension, chest pain and/or angina, bradycardia, headache. Tafluprost: headache.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. The risk of toxicity from inadvertent ingestion is low because the amount contained in the bottles of ophthalmic solution is small. LATANOPROST: There are no reports of ingestion or ocular administration of large doses of latanoprost in humans. No adverse effects were reported after intravenous infusion of up to 3 mcg/kg (produced greater than 200 times therapeutic plasma level) in healthy volunteers. Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating. However, latanoprost is only available as ophthalmic solutions.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) LATANOPROST
    a) ALTERED PIGMENTATION: Latanoprost may gradually (months to years) increase brown pigment in the iris by increasing the number of melanosomes in melanocytes. The increased pigmentation may be permanent (Prod Info Xalatan(R) ophthalmic solution, 2009).
    b) Ocular signs and symptoms reported in 5% to 15% of patients during a controlled clinical trial included: blurred vision, burning, stinging, conjunctival hyperemia, foreign body sensation, increased pigmentation, punctate epithelial keratopathy (Prod Info Xalatan(R) ophthalmic solution, 2009). Other effects reported in postmarketing experience have included: ocular hypotony, choroidal effusions, dendritiform epitheliopathy, and recurrent cystoid macular edema (Rowe et al, 1997; Sudesh et al, 1993).
    c) DENDRITIFORM EPITHELIOPATHY was reported in 4 patients following ophthalmic use; symptoms resolved with discontinuation of drug therapy (Sudesh et al, 1993).
    2) BIMATOPROST
    a) Iris pigmentation was reported in 1% to 10% of patients who were treated with bimatoprost ophthalmic solution for elevated intraocular pressure in clinical trials. Increase in iris pigmentation occurs due to increased melanin content in the stromal melanocytes of the iris and may not be visible for several months or years. Iris pigmentation resulting from bimatoprost ophthalmic solution is often permanent (Prod Info LUMIGAN(R) ophthalmic solution, 2010).
    b) Conjunctival hyperemia was reported in 25% to 45% of patients who were treated with bimatoprost ophthalmic solution for elevated intraocular pressure in clinical trials. Allergic conjunctivitis, eye discharge, tearing, photophobia, ocular dryness, visual disturbance, ocular burning, eye pain, blepharitis, cataracts, superficial punctate keratitis, eyelid erythema, pruritus, and conjunctival edema were also reported in 1% to 10% of patients (Prod Info LUMIGAN(R) ophthalmic solution, 2010).
    c) Macular edema, including cystoid macular edema, has been reported in patients treated with bimatoprost ophthalmic solution for elevated intraocular pressure, particularly in those with known risk factors (aphakia or pseudophakia with a torn posterior lens capsule) (Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info LATISSE(R) ophthalmic solution, 2009).
    d) BIMATOPROST/TIMOLOL: CONJUNCTIVAL HYPEREMIA: Based on 12-month clinical data, conjunctival hyperemia was the most common adverse effect, reported in approximately 26% of patients treated with bimatoprost/timolol ophthalmic solution. Discontinuation of therapy due to conjunctival hyperemia occurred in 1.5% of patients (Prod Info GANFORT ophthalmic solution, 2011).
    e) BIMATOPROST/TIMOLOL: In clinical trials, superficial punctate keratitis, corneal erosion, burning sensation, eyelid pruritus, eye dryness, eye pain, photophobia, eye discharge, visual disturbances, eyelid erythema, and blepharal pigmentation were reported in up to 10% of patients who received bimatoprost/timolol maleate ophthalmic solution (Prod Info GANFORT ophthalmic solution, 2011).
    1) The preservative benzalkonium chloride has been reported to cause punctate keratopathy and toxic ulcerative keratopathy (Prod Info GANFORT ophthalmic solution, 2011).
    3) TAFLUPROST
    a) Tafluprost ophthalmic solution has been associated with changes in pigmentation, occurring predominately on the iris, periorbital tissue (eyelid), and eyelashes, due to increased melanin content in the melanocytes. Pigmentation increases with continued use and is likely to be permanent in the iris while pigment changes of the periorbital tissue and eyelashes are likely to resolve after discontinuation in some patients. The long term effects of increased pigmentation are unknown (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    b) Macular edema, including cystoid macular edema, has been reported with prostaglandin F2 alpha analogs (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    c) In 5 controlled clinical trials (n=905), conjunctival hyperemia was the most commonly reported adverse event, occurring in 4% to 20% of patients receiving 0.0015% tafluprost ophthalmic solution (preservative-free or preservative-containing) for up to 24 months. Discontinuation due to ocular events occurred in approximately 1% of patients. The following adverse effects were also reported: ocular stinging and irritation (7%), ocular pruritus, including allergic conjunctivitis (5%), cataracts (3%), dry eye (3%), ocular pain (3%), and blurred vision (2%) (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    d) During postmarketing surveillance, changes in the periorbital and lid tissue, including deepening of the eyelid sulcus, have been reported with prostaglandin analogs (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    4) TRAVOPROST
    a) Iris discoloration was reported in 1% to 4% of patients who were treated with travoprost ophthalmic solution 0.004% in clinical trials. Increase in iris pigmentation occurs due to increased melanin content in melanocytes of the iris and may not be visible for several months or years. Iris pigmentation resulting from travoprost ophthalmic solution is likely permanent, while pigmentation of periorbital tissue and eyelash are reversible in some patients. Brown pigmentation usually spreads concentrically toward the periphery of the iris with browning of parts or the entirety of the iris. Nevi and freckles of the iris appear to be spared from this pigmentation (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    b) Ocular hyperemia was the most common adverse reaction during controlled clinical trials and was reported in 30% to 50% of patients treated with travoprost ophthalmic solution 0.004%. Ocular pain, Foreign body sensation, eye discomfort, ocular pruritus, and decreased visual acuity were reported in 5% to 10% of patients receiving travoprost. Blepharitis, abnormal vision, blurred vision, dry eye, lid margin crusting, photophobia, subconjunctival hemorrhage and tearing, ocular inflammation, cataract, conjunctivitis, keratitis, and corneal staining were reported in 1% to 4% of patients receiving travoprost (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    c) Macular edema, including cystoid macular edema, has been reported in patients treated with travoprost ophthalmic solution, particularly in those with known risk factors (aphakia or pseudophakia with a torn posterior lens capsule) (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    d) CASE REPORT: The day after a LASIK (laser-assisted in situ keratomileusis) surgery, a 25-year-old woman developed severe abdominal cramps, sudden severe menstrual bleeding, and hyperemia of the eyes after inadvertently using travoprost every 15 minutes for 7 hours, instead of artificial tears. It was estimated that she used more than half of the 2.5 mL bottle of travoprost. Her symptoms improved an hour after the discontinuation of travoprost, and resolved the next day (Goodwin & Erickson, 2014).
    e) CASE REPORT: A 70-year-old man with open-angle glaucoma in both eyes developed acute anterior uveitis and corneal edema within 2 days after switching from a regimen of timolol maleate 0.5% and brimonidine to travoprost monotherapy. Treatment with travoprost was discontinued and lotepredinol etabonate therapy was initiated. The patient's discomfort resolved within 10 days, visual acuity improved, and corneal edema was clearing (Faulkner & Burk, 2003).
    f) TRAVOPROST/TIMOLOL: CONJUNCTIVAL HYPEREMIA: In 3 clinical studies (n=372), 11.8% of patients who received travoprost/timolol maleate (polyquaternium-1-preserved) for up to 12 months experienced hyperemia of the eye, including conjunctival or ocular hyperemia. In the majority of cases (91%), hyperemia of the eye did not result in discontinuation of therapy (Prod Info DuoTrav ophthalmic solution, 2012).
    g) TRAVOPROST/TIMOLOL: Eye pain, ocular discomfort, dry eye, and eye pruritus were reported in up to 10% of patients who received travoprost/timolol maleate (polyquaternium-1-preserved) in clinical studies (Prod Info DuoTrav ophthalmic solution, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: CASE REPORTS: Elevated blood pressure of 200/120 mm Hg and 260/120 mm Hg occurred within 4 days and 6 weeks, respectively, of the start of latanoprost in 2 elderly patients with no prior history of hypertension. Blood pressure returned to baseline with drug cessation (Peak & Sutton, 1998).
    1) LACK OF EFFECT: Other studies have reported that ophthalmic use of latanoprost has NOT been associated with significant changes in systolic or diastolic blood pressure or heart rate (Rulo et al, 1994; Kjellgren et al, 1995; Alm et al, 1993; Alm & Stjernschantz, 1995a).
    b) TRAVOPROST: Hypertension occurred in 1% to 5% of patients treated with travoprost during clinical studies (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: Chest pain and/or angina pectoris were reported in 1% to 2% of patients treated with latanoprost (Prod Info Xalatan(R) ophthalmic solution, 2009).
    b) LATANOPROST: Onset of angina was reported in a 72-year-old man who began receiving latanoprost 0.005% once daily. The angina resolved upon discontinuation of latanoprost (Mitra et al, 2001).
    c) TRAVOPROST: Chest pain and/or angina occurred in 1% to 5% of patients treated with travoprost during clinical studies (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) TRAVOPROST: Bradycardia has occurred in 1% to 5% of patients treated with travoprost during clinical studies (Prod Info TRAVATAN(R) ophthalmic solution, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) INTERMENSTRUAL BLEEDING - IRREGULAR
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: The day after a LASIK (laser-assisted in situ keratomileusis) surgery, a 25-year-old woman developed severe abdominal cramps, sudden severe menstrual bleeding, and hyperemia of the eyes after inadvertently using travoprost every 15 minutes for 7 hours, instead of artificial tears. It was estimated that she used more than half of the 2.5 mL bottle of travoprost. Her symptoms improved an hour after the discontinuation of travoprost, and resolved the next day (Goodwin & Erickson, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: CASE REPORT: A 78-year-old woman developed a facial rash over her forehead, cheeks, and nose 5 days after drug initiation. Although a causal relation could not be determined, the rash progressed until drug cessation; symptoms may have been related to a hypersensitivity response (Rowe et al, 1997).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused sweating (Prod Info Xalatan(R) ophthalmic solution, 2009).
    C) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused hot flashes (Prod Info Xalatan(R) ophthalmic solution, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: Muscle, joint and back pain have been reported by 1 to 2% of patients treated with latanoprost (Prod Info Xalatan(R) ophthalmic solution, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Bimatoprost, latanoprost, tafluprost, and travoprost are classified as FDA pregnancy category C. The use of these drugs has not been studied in pregnant woman. In animal studies, skeletal malformations have been observed with tafluprost and travoprost. Increased incidences of fetal death and reduced birth weight have been observed with bimatoprost, latanoprost, tafluprost, and travoprost. It is not known whether any of these drugs or their metabolites are excreted in human milk. However, bimatoprost, tafluprost, and travoprost were excreted in breast milk in animal studies. Bimatoprost, latanoprost, tafluprost, and travoprost did not impair fertility in animal studies. However, an increase in post-implantation losses was noted with tafluprost and travoprost, and travoprost caused a reduction in the mean number of corpora lutea.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) TAFLUPROST
    a) RABBITS: There was an increased incidence of skull, brain and spine malformations in rabbits after IV tafluprost was administered during embryo-fetal development. The rabbits were given tafluprost 0.03 mcg/kg/day, which corresponded to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure based on Cmax. No effects were noted when the rabbits were given 0.01 mcg/kg/day of IV tafluprost, and the maternal plasma levels of tafluprost acid were below the lower level of quantification (20 picograms/mL) (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    b) RATS: There was an increased incidence of vertebral skeletal abnormalities in rats after IV tafluprost was administered during embryo-fetal development. No teratogenic effects were noted when the rats were given 3 mcg/kg/day of IV tafluprost, which corresponded to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    2) TRAVOPROST
    a) RATS/MICE: An increase in the incidence of skeletal malformations and external and visceral malformations (fused sternebrae, domed head, and hydrocephaly) were observed in rats given IV travoprost doses up to 10 mcg/kg/day (250 times the maximum recommended human ocular dose (MRHOD)). Travoprost was not teratogenic in rats and mice at IV doses up to 3 mcg/kg/day (75 times the MRHOD) or subQ doses up to 1 mcg/kg/day (25 times the MRHOD), respectively (Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of bimatoprost, latanoprost, tafluprost, or travoprost administration in pregnant women (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006; Prod Info Xalatan(R) ophthalmic solution, 2006; Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified bimatoprost, latanoprost, tafluprost, and travoprost as FDA pregnancy category C (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006; Prod Info Xalatan(R) ophthalmic solution, 2006; Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    C) ANIMAL STUDIES
    1) BIMATOPROST
    a) RATS/MICE: Abortion was observed after pregnant mice and rats were treated with oral doses of bimatoprost of at least 33 or 97 times, respectively, the intended human exposure based on blood AUC levels after ophthalmic administration to the cornea or conjunctival sac. When rats and mice were given oral bimatoprost at doses 41 times the intended human exposure, reduced gestation time, increased incidence of fetal death, late resorptions, and pup mortality, and reduced pup birth weight were observed (Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006).
    2) LATANOPROST
    a) RABBITS: Four of 16 pregnant rabbits given 80 times the maximum recommended human dose of latanoprost produced no viable offspring. The lowest non-embryolethal dose of latanoprost was 15 times the maximum recommended human dose (Prod Info Xalatan(R) ophthalmic solution, 2006).
    3) TAFLUPROST
    a) RABBITS: An increase in post-implantation losses was noted in rabbits after IV tafluprost was administered during embryo-fetal development. The rabbits were given tafluprost 0.03 mcg/kg/day, which corresponded to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure based on Cmax. No effects were noted when the rabbits were given 0.01 mcg/kg/day of IV tafluprost, and the maternal plasma levels of tafluprost acid were below the lower level of quantification (20 picograms/mL) (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    b) RATS: An increase in post-implantation losses and reductions in fetal body weight were noted in rats after IV tafluprost was administered during embryo-fetal development. No effects were noted when the rats were given 3 mcg/kg/day of IV tafluprost, which corresponded to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    c) RATS: Increased mortality of newborns, decreased body weight, and delayed pinna unfolding were observed in the offspring of rats after maternal exposure to IV tafluprost during pregnancy in a prenatal and postnatal development study. Intravenous tafluprost 0.3 mcg/kg/day, which is greater than 3 times the maximum recommended clinical dose based on body surface area, was the dose where no adverse effects were observed (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    4) TRAVOPROST
    a) RATS/MICE: An increase in post-implantation losses and a decrease in fetal viability occurred in rats and mice at IV doses of less than 3 mcg/kg/day (75 times MRHOD) and subQ doses of less than 0.3 mcg/kg/day (7.5 times MRHOD) in rats and mice, respectively. The incidence of postnatal mortality was increased and neonatal body weight gain was decreased in the offspring of female rats that received travoprost subQ at doses of 0.12 mcg/kg/day or greater (3 times the MRHOD) from day 7 of pregnancy to day 21 of lactation. Neonatal development was also adversely affected as evidenced by delayed eye opening, pinna detachment and preputial separation, and decreased motor activity (Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BIMATOPROST
    a) It is not known whether bimatoprost, latanoprost, tafluprost, or travoprost are excreted in human milk (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006; Prod Info Xalatan(R) ophthalmic solution, 2006; Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    B) ANIMAL STUDIES
    1) BIMATOPROST
    a) In animal studies, bimatoprost has been shown to be excreted into breast milk (Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006).
    2) TAFLUPROST
    a) In lactating rats, radiolabeled tafluprost and/or its metabolites were excreted in breast milk (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    3) TRAVOPROST
    a) In lactating rats, radiolabeled travoprost and/or its metabolites were shown to be excreted in breast milk (Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) BIMATOPROST
    a) RATS: Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (Prod Info LATISSE(TM) ophthalmic solution, 2008; Prod Info LUMIGAN(R) ophthalmic solution, 2006).
    2) LATANOPROST
    a) In animal studies, latanoprost was not found to affect male or female fertility (Prod Info Xalatan(R) ophthalmic solution, 2006).
    3) TAFLUPROST
    a) RATS: No adverse effects on mating performance or fertility were observed when rats were given IV tafluprost at a dose of 100 mcg/kg/day, which is over 14,000 times the maximum clinical exposure based on plasma Cmax or over 3600 times based on the plasma AUC (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    4) TRAVOPROST
    a) RATS: Travoprost did not affect mating or fertility in male or female rats at subQ doses up to 10 mcg/kg/day (250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day (MRHOD)). However, at 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at a dose of 3 mcg/kg/day (75 times the MRHOD) (Prod Info TRAVATAN(R) Z ophthalmic solution, 2006).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS130209-82-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers of bimatoprost, latanoprost, tafluprost, and travoprost do not report any carcinogenic potentials in humans.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) No carcinogenicity studies in humans have been reported.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 micrograms/kilogram/day (approximately 2,800 times the recommended maximum human dose) for up to 20 and 24 months, respectively (Prod Info Xalatan(R), latanoprost, 1999).
    B) LACK OF EFFECT
    1) BIMATOPROST
    a) There was no evidence of carcinogenicity observed in mice and rats administered oral gavage doses of bimatoprost up to 2 mg/kg/day and 1 mg/kg/day, respectively (over 192 and 291 times the recommended human dose based on AUC, respectively), for a duration of 104 weeks (Prod Info LUMIGAN(R) ophthalmic solution, 2010a; Prod Info LATISSE(R) ophthalmic solution, 2011).
    2) LATANOPROST
    a) There was no evidence of carcinogenicity in mice or rats administered oral gavage doses of latanoprost up to 170 mcg/kg/day (approximately 2800 time the maximum recommended human dose) for up to 20 and 24 months, respectively (Prod Info Xalatan(R) ophthalmic solution, 2009).
    3) TAFLUPROST
    a) There was no evidence of carcinogenicity observed in mice and rats administered subQ doses of tafluprost up to 100 mcg/kg/day and 30 mcg/kg/day, respectively (over 1300 and 1600 times the maximum clinical exposure based on plasma AUC, respectively), for a period of 24 months (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    4) TRAVOPROST
    a) A 2-year carcinogenicity study in mice and rats administered subQ doses of travoprost 10, 30, or 100 mcg/kg/day (up to 400 times the maximum recommended human ocular dose) revealed no evidence of carcinogenicity (Prod Info TRAVATAN(R) ophthalmic solution, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INFECTIONS
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: The most common (approximately 4%) systemic adverse event seen with latanoprost during clinical trials were upper respiratory tract infection/cold/flu. The occurrence of these symptoms in control patients was not stated (Prod Info Xalatan(R) ophthalmic solution, 2009).
    b) BIMATOPROST: Infections, primarily colds and upper respiratory tract infections, were reported in approximately 10% of patients who were treated with bimatoprost ophthalmic solution for elevated intraocular pressure in clinical trials (Prod Info LUMIGAN(R) ophthalmic solution, 2010).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: The ocular administration of latanoprost to patients with bronchial asthma did not induce bronchoconstriction (Prod Info Xalatan(R) ophthalmic solution, 2009).
    b) This class of prostaglandin (PGF-2-alpha) causes bronchoconstriction in humans (1000 times more potent than histamine) (Hardman et al, 1996).
    2) WITH POISONING/EXPOSURE
    a) LATANOPROST: Intravenous doses of up to 3 mcg/kg of latanoprost (produced mean plasma concentrations higher than 200 times during clinical treatment) in healthy volunteers produced NO respiratory or adverse reactions (Prod Info Xalatan(R) ophthalmic solution, 2009).
    C) RESPIRATORY FAILURE
    1) WITH THERAPEUTIC USE
    a) LATANOPROST: In postmarketing experience, reports of asthma, exacerbation of asthma and dyspnea have occurred with therapeutic use; the frequency of these events is unknown (Prod Info Xalatan(R) ophthalmic solution, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) LATANOPROST: Intravenous doses of 5.5 to 10 micrograms/kilogram in healthy volunteers caused dizziness (Prod Info Xalatan(R) ophthalmic solution, 2009).
    B) FATIGUE
    1) WITH POISONING/EXPOSURE
    a) LATANOPROST: Intravenous doses of 5.5 to 10 micrograms/kilogram in healthy volunteers caused fatigue (Prod Info Xalatan(R) ophthalmic solution, 2009).
    C) HEADACHE
    1) WITH THERAPEUTIC USE
    a) BIMATOPROST: Headache was reported in 1% to 5% of patients with elevated intraocular pressure who were treated with bimatoprost ophthalmic solution in clinical trials (Prod Info LUMIGAN(R) ophthalmic solution, 2010).
    b) LATANOPROST: Headache has been reported during topical therapy with latanoprost (Weston, 2001; Nagasubramanian et al, 1993a).
    c) TAFLUPROST: In 5 controlled clinical trials (n=905), headache was reported in 6% of patients receiving 0.0015% tafluprost ophthalmic solution (preservative-free or preservative-containing) for up to 24 months (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    d) TRAVOPROST: Headache occurred in 1% to 5% of patients treated with travoprost during clinical studies (Prod Info TRAVATAN(R) ophthalmic solution, 2011).
    D) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) BIMATOPROST: Asthenia was reported in 1% to 5% of patients who were treated with bimatoprost ophthalmic solution for elevated intraocular pressure in clinical trials (Prod Info LUMIGAN(R) ophthalmic solution, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH POISONING/EXPOSURE
    a) Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused nausea (Prod Info Xalatan(R) ophthalmic solution, 2009).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain (Prod Info Xalatan(R) ophthalmic solution, 2009).
    b) CASE REPORT: The day after a LASIK (laser-assisted in situ keratomileusis) surgery, a 25-year-old woman developed severe abdominal cramps, sudden severe menstrual bleeding, and hyperemia of the eyes after inadvertently using travoprost every 15 minutes for 7 hours, instead of artificial tears. It was estimated that she used more than half of the 2.5 mL bottle of travoprost. Her symptoms improved an hour after the discontinuation of travoprost, and resolved the next day (Goodwin & Erickson, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) BIMATOPROST: Elevated liver enzymes were reported in 1% to 5% of patients who were treated with bimatoprost ophthalmic solution for elevated intraocular pressure in clinical trials (Prod Info LUMIGAN(R) ophthalmic solution, 2010).

Genotoxicity

    A) BIMATOPROST: No clastogenic or mutagenic effects were noted with bimatoprost in the following tests: Ames test, mouse lymphoma test, or in vivo mouse micronucleus test (Prod Info LUMIGAN(R) ophthalmic solution, 2010a; Prod Info LATISSE(R) ophthalmic solution, 2011)
    B) LATANOPROST: In vitro studies with human lymphocytes revealed chromosome aberrations. There was no evidence of mutagenicity with latanoprost in the following test: bacteria, mouse lymphoma, or mouse micronucleus tests (Prod Info Xalatan(R) ophthalmic solution, 2009).
    C) TAFLUPROST: No clastogenic or mutagenic effects were noted with tafluprost in the following tests: in vitro microbial mutagenesis assay, in vitro chromosomal aberration assay in Chinese hamster lung cells, and in vivo mouse micronucleus assay in bone marrow (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    D) TRAVOPROST: There was no evidence of mutagenicity with travoprost in the following tests: Ames test, mouse micronucleus test, or rat chromosome aberration assay (Prod Info TRAVATAN(R) ophthalmic solution, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or for whom diagnosis is unclear. Consult an ophthalmologist for managing a patient with severe eye irritation.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with symptoms or a deliberate overdose should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Although these agents have not been associated with oral toxicity, inadvertent ingestion of the ophthalmic solution may occur. Due to limited expected toxicity, gastrointestinal decontamination is not routinely recommended. Since the amounts of active ingredient available in ophthalmic solutions are very small, acute overdose in adults is unlikely to result in clinically significant adverse events. OCULAR: Flush eyes with copious amounts of water; if symptoms persist an eye exam may be indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Monitor vital signs in symptomatic patients.
    3) Monitor serum electrolytes in patients with significant vomiting.
    B) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is not recommended.

Range Of Toxicity

Summary

    A) TOXICITY: No toxic ingestions have been reported. The risk of toxicity from inadvertent ingestion is low because the amount contained in the bottles of ophthalmic solution is small. LATANOPROST: Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating. No adverse effects were reported after intravenous infusion of up to 3 mcg/kg (produced greater than 200 times therapeutic plasma level) in healthy volunteers.
    B) THERAPEUTIC DOSES: ADULTS: ALL AGENTS: 1 drop in affected eye(s) once daily in the evening. CHILDREN: LATISSE(R): In a 16-week double-masked, randomized, vehicle-controlled study, bimatoprost ophthalmic solution (0.03%) was administered to pediatric patients (age range, 5 to 17 years) with alopecia areata (n=15) or after chemotherapy (n=16), and to adolescents (age range, 15 to 17 years) with hypotrichosis (n=40). There were no new safety issues in these patients. ALL OTHER AGENTS: Safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) ALL AGENTS: 1 drop in affected eye(s) once daily in the evening (Prod Info IZBA ophthalmic solution, 2014; Prod Info DuoTrav ophthalmic solution, 2012; Prod Info GANFORT ophthalmic solution, 2011; Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info TRAVATAN(R) ophthalmic solution, 2011; Prod Info LATISSE(R) ophthalmic solution, 2014; Prod Info Xalatan(R) ophthalmic solution, 2009)
    7.2.2) PEDIATRIC
    A) ALL OTHER AGENTS: Safety and effectiveness have not been established in pediatric patients (Prod Info DuoTrav ophthalmic solution, 2012; Prod Info GANFORT ophthalmic solution, 2011; Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info TRAVATAN(R) ophthalmic solution, 2011; Prod Info Xalatan(R) ophthalmic solution, 2009).
    B) LATISSE(R): In a 16-week double-masked, randomized, vehicle-controlled study, bimatoprost ophthalmic solution (0.03%) was administered to pediatric patients (age range, 5 to 17 years) with alopecia areata (n=15) or after chemotherapy (n=16), and to adolescents (age range, 15 to 17 years) with hypotrichosis (n=40). There were no new safety issues in these patients (Prod Info LATISSE(R) ophthalmic solution, 2014).
    C) TRAVOPROST: Safety and effectiveness have not been established in pediatric patients less than 16 years of age (Prod Info IZBA ophthalmic solution, 2014)

Minimum Lethal Exposure

    A) LATANOPROST: A lethal dose of latanoprost has not been determined.
    B) UNOPROSTONE: A toxic dose has not been established. The risk of adverse effects due to accidental oral ingestion is considered low due to the amount of active ingredient in each bottle (7.5 mg in a 7.5 mL bottle) (Prod Info Rescula(R), 2001).

Maximum Tolerated Exposure

    A) LATANOPROST: Intravenous doses of 5.5 to 10 mcg/kg in healthy volunteers caused abdominal pain, dizziness, fatigue, hot flashes, nausea, and sweating. No adverse effects were reported after intravenous infusion of up to 3 mcg/kg (produced greater than 200 times therapeutic plasma level) in healthy volunteers (Prod Info Xalatan(R) ophthalmic solution, 2009).
    B) The largest dose of latanoprost reported is 4 mcg/day (based on twice daily administration of a 0.006% solution) (Nagasubramanian et al, 1993).

Workplace Standards

    A) ACGIH TLV Values for CAS130209-82-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS130209-82-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS130209-82-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS130209-82-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bimatoprost, latanoprost, tafluprost, and travoprost are prostaglandin analogs and selective FP prostanoid receptor agonist. Latanoprost, tafluprost, and travoprost reduce intraocular pressure (IOP) by increasing uveoscleral outflow. Bimatoprost lowers IOP by increasing the outflow of aqueous humor through both the trabecular meshwork and uveoscleral drainage systems. The exact mechanism of action for bimatoprost in stimulating eyelash growth is unknown it may work by increasing the duration and the percentage of hairs in the anagen or growth phase (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012; Prod Info TRAVATAN(R) ophthalmic solution, 2011; Prod Info LUMIGAN(R) ophthalmic solution, 2010; Prod Info LATISSE(R) ophthalmic solution, 2009; Prod Info Xalatan(R) ophthalmic solution, 2009).

Physicochemical

Physical Characteristics

    A) LATANOPROST: colorless to slightly yellow oil; very soluble in acetonitrile; freely soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol; and practically insoluble in water. The ophthalmic solution has an osmolality of approximately 267 milliosmoles/kg (Prod Info Xalatan(R) ophthalmic solution, 2012).
    B) TAFLUPROST: colorless to light yellow viscous liquid, practically insoluble in water. The ophthalmic solution has an osmolality of 260 to 300 milliosmoles/kg (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012).
    C) TRAVOPROST: clear, colorless to slightly yellow oil; very soluble in acetonitrile, in chloroform, in methanol, and in octanol; and practically insoluble in water. The ophthalmic solution has an osmolality of approximately 290 milliosmoles/kg (Prod Info IZBA ophthalmic solution, 2014; Prod Info TRAVATAN(R) ophthalmic solution, 2011).

Ph

    A) LATANOPROST: approximately 6.7 (ophthalmic solution) (Prod Info Xalatan(R) ophthalmic solution, 2012)
    B) TAFLUPROST: 5.5 to 6.7 (ophthalmic solution) (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012)
    C) TRAVOPROST: approximately 6.8 (ophthalmic solution 0.003%) (Prod Info IZBA ophthalmic solution, 2014); approximately 6 (ophthalmic solution 0.004%) (Prod Info TRAVATAN(R) ophthalmic solution, 2011)

Molecular Weight

    A) LATANOPROST: 432.58 (Prod Info Xalatan(R) ophthalmic solution, 2012)
    B) TAFLUPROST: 452.53 (Prod Info ZIOPTAN(TM) ophthalmic solution, 2012)
    C) TRAVOPROST: 500.55 (Prod Info IZBA ophthalmic solution, 2014)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
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