Antiglaucoma Agents, Cholinergic, Long-acting (Ophthalmic )

This monograph includes information on the following:

1) Demecarium  
2) Echothiophate
3) Isoflurophate * 


INN:
Echothiophate— Ecothiopate Iodide {88}2

BAN:
Isoflurophate—Dyflos {88}1

VA CLASSIFICATION
Primary: OP118
Secondary: OP900; DX900

Commonly used brand name(s): Diflupyl3; Humorsol1; Phospholine Iodide2.

Other commonly used names are:
DFP — isoflurophate
, difluorophate —isoflurophate
, dyflos —isoflurophate
, and ecothiopate iodide —echothiophate
.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antiglaucoma agent (ophthalmic)—

cyclostimulant (accommodative esotropia)—

diagnostic aid (accommodative esotropia)—

Indications
{88}0
Accepted

Note: Because isoflurophate is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.

Glaucoma (treatment)—Demecarium, echothiophate, and [isoflurophate]1 , which are long-acting cholinesterase inhibitors, {03}9 {03}8 {03}7 are potent miotics. {03}6 {03}5 {03}4 Because of their toxicity, {03}3 they should be reserved for use in patients with open-angle glaucoma or other chronic glaucomas not satisfactorily controlled with the short-acting miotics and other agents. {03}2 {03}1 {03}0 {06}9 {06}8 {06}7 {06}6 {06}5



Glaucoma, open-angle (treatment): Demecarium, echothiophate, and [isoflurophate]1 are indicated in the treatment of chronic open-angle glaucoma. {06}4 {06}3 {06}2 {06}1 {06}0 {88}9 {88}8 {88}7 {88}6 {88}5 {88}4



Glaucoma, angle-closure, after iridectomy (treatment): {88}3 {88}2 {88}1 {88}0 {61}9 {61}8 {61}7 {61}6 Demecarium, echothiophate, and [ isoflurophate]1 are indicated in the treatment of subacute or chronic angle-closure glaucoma following iridectomy {61}5 {61}4 {61}3 {61}2 {61}1 if continued drug therapy is required and short-acting miotics and other agents are inadequate. {61}0 Long-acting cholinesterase inhibitors are usually {66}9 not recommended for use in angle-closure glaucoma prior to iridectomy, {66}8 {66}7 {66}6 {66}5 {66}4 because they may increase the pupillary {66}3 block. {66}2 {66}1 {66}0 {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 However, echothiophate may be indicated in subacute or chronic angle-closure glaucoma when surgery is refused or contraindicated {03}3 {03}2 in the informed patient {03}1 who understands the increased risk of pupillary block. {03}0 {88}9



Glaucoma, secondary {88}8 {88}7 {88}6 {88}5 (treatment): Echothiophate is indicated in the treatment of certain nonuveitic secondary types of glaucoma, especially glaucoma following cataract surgery. {88}4 {88}3 {88}2 {88}1 {88}0

Esotropia, accommodative (diagnosis) or {03}9 {03}8 {03}7 {03}6 {03}5 {03}4 {03}3 {03}2 {03}1
Esotropia, accommodative (treatment) {03}0 {88}9 {88}8 {88}7 {88}6 {88}5 {88}4 {88}3 {88}2—Demecarium, echothiophate, and [isoflurophate ]1 are indicated in the diagnosis of accommodative esotropia. {88}1 {88}0 {66}9 {66}8 Demecarium and [isoflurophate ]1 are indicated in the treatment of accommodative esotropia uncomplicated by amblyopia (impairment of vision) or anisometropia (difference in the refractive power of the eyes). {66}7 {66}6 {66}5 {66}4 {66}3 Echothiophate may be {66}2 {66}1 indicated in the treatment of concomitant esotropias with a significant accommodative component. {66}0 {85}9 {85}8

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Demecarium bromide: 716.60 {85}7 {85}6 {85}5 {85}4
    Echothiophate iodide: 383.23 {85}3
    Isoflurophate: 184.15 {85}2 {85}1

Mechanism of action/Effect:

Demecarium, echothiophate, and isoflurophate are indirect-acting parasympathomimetic agents, which are also known as cholinesterase inhibitors and anticholinesterases. {85}0 {88}9 {88}8 {88}7 Cholinesterase inhibitors prolong the effect of acetylcholine, which is released at the neuroeffector junction of parasympathetic postganglion nerves, {88}6 by inactivating the cholinesterases that break it down. {88}5 {88}4 {88}3 Echothiophate and isoflurophate primarily inactivate pseudocholinesterase and incompletely inactivate acetylcholinesterase, {88}2 {88}1 whereas demecarium inactivates both pseudocholinesterase and acetylcholinesterase. {88}0 {85}9 In the eye, this causes constriction of the iris sphincter muscle (causing miosis) and the ciliary muscle (affecting {85}8 the accommodation reflex and causing a spasm of the {85}7 focus to near vision). {85}6 The outflow of the aqueous humor is facilitated, which leads to a reduction in intraocular pressure. {85}5 {85}4 {85}3 Of the two actions, the effect on {85}2 {85}1 the accommodation reflex is the more transient and generally disappears before termination of the miosis. {85}0




Antiglaucoma agent (ophthalmic)—Cholinesterase inhibitors reduce intraocular pressure in both types of primary glaucoma (i.e., angle-closure glaucoma and open-angle glaucoma) primarily by lowering the resistance to the outflow of the aqueous humor. {85}9 In angle-closure glaucoma, the abnormal contact between the peripheral iris and the peripheral cornea blocks the access of the anterior chamber of aqueous humor to the trabecular meshwork. {85}8 In open-angle glaucoma, the block is between the trabecular meshwork and the canal of Schlemm. {85}7 Effects on the volumes of the various intraocular vascular beds (e.g., those of the iris and the ciliary body) and on the rate of secretion of the aqueous humor into the posterior chamber may contribute secondarily to the lowering of pressure. {85}6 Contraction of {85}5 the ciliary muscle may act to increase {85}4 tone and alignment of the trabecular meshwork, {85}3 which improves outflow of aqueous humor through the meshwork {85}2 to the canal of Schlemm. {85}1 {85}0 {93}9 {93}8 The longitudinal ciliary muscle is the major component; {93}7 the iris sphincter is not {93}6 relevant in open-angle glaucoma, but its contraction may improve (or worsen) {93}5 angle-closure glaucoma. {93}4 {93}3 In angle-closure glaucoma, the outflow of the aqueous humor is facilitated by the drug-induced contraction of the iris sphincter muscle. {93}2 {93}1 This contraction prevents the iris from blocking the entrance to the trabecular space at the canal of Schlemm by lessening pupillary block. {93}0 However, extreme miosis may actually increase pupillary block, thus worsening angle-closure glaucoma prior to iridectomy. {93}9 {93}8 {93}7 In open-angle glaucoma, although there is no physical obstruction at the entrance to the trabecular space, the trabeculae, which are a meshwork of small-diameter pores, increase their resistance {93}6 {93}5 {93}4 {93}3 and lose their permeability. {93}2 {93}1




Cyclostimulant (accommodative esotropia)—Cholinesterase inhibitors reduce the amount of convergence associated with a given amount of accommodation, thereby reducing the degree of esotropia. {93}0




Diagnostic aid (accommodative esotropia)—See Cyclostimulant (accommodative esotropia) above. An accommodative factor is demonstrated if the eyes become better aligned. {93}9 {93}8 {93}7

Onset of action:
{93}6
Miosis—Less than 1 hour. {93}5

Reduction in intraocular pressure—Within 4 hours. {93}4 {93}3 {93}2 {93}1

Time to peak effect:
{93}0
Miosis—Within 2 hours. {03}9

Reduction in intraocular pressure—Within 24 hours. {03}8

Duration of action:
{03}7
Miosis—Up to 1 month. {03}6

Reduction in intraocular pressure—Up to 1 month, but usually 24 to 48 hours. {03}5 {03}4


Precautions to Consider

Carcinogenicity/Mutagenicity

Studies have not been done for demecarium, echothiophate, and isoflurophate. {03}3 {03}2 {03}1 {03}0 {88}9 {88}8

Pregnancy/Reproduction
Fertility—
Studies have not been done for demecarium, echothiophate, and isoflurophate. {88}7 {88}6 {88}5 {88}4 {88}3 {88}2 {88}1

Pregnancy—

Demecarium and isoflurophate

Use of demecarium and isoflurophate is not recommended during pregnancy, because of the toxicity of cholinesterase inhibitors in general. {88}0 {03} {88} {90} {91} If pregnancy occurs while one of these medications is being administered, the patients should be advised of the potential hazard to the fetus. {02} {03} {88} {90} {91}

FDA Pregnancy Category X. {02} {03} {88} {90} {91}



Echothiophate

Studies have not been done in humans. {04} {89} However, this ophthalmic medication may be systemically absorbed {36} and should be administered to pregnant women only if clearly needed. {04} {89}

Studies have not been done in animals. {04} {89}

FDA Pregnancy Category C. {04} {89}


Note: Although the FDA Pregnancy Categories are different for the above medications, some experts believe that all three medications should be rated the same, namely, Category X. {29}


Breast-feeding

Problems in humans have not been documented; however, these ophthalmic medications may be systemically absorbed. {02} {03} {04} {36} {85} Because of the toxicity of cholinesterase inhibitors in general, {02} {03} {85} and the potential for serious adverse reactions in the nursing infant, {02} {03} {85} some clinicians believe that {67} {85} a decision should be made whether to discontinue nursing or discontinue the medication. {02} {03} {04} {85} {88} {89} {90} {91} Other clinicians believe that the concentration of medication in breast milk would be so minute that it would not present a problem. {67} {85}

Pediatrics

The iris cysts at the pupil margins {67} that may occur following prolonged use of these medications occur frequently {67} {85} in children. {02} {03} {04} {36} {43} {88} {90} {91} The most common systemic effects, especially in children, are nausea, vomiting, diarrhea, and stomach cramps or pain. {44} No other information is available on whether the risk of adverse effects is increased in children, except that one drop of medication will result in a greater systemic dose per kg of body weight in a child than in an adult. {67} {85} Because of the toxicity of these medications, {02} {03} they should be used with caution, after less toxic alternatives have been considered and/or found ineffective. Recommended doses should not be exceeded, and the patient should be carefully monitored during therapy.


Geriatrics


No information is available on whether the risk of adverse effects from long-acting cholinergic antiglaucoma agents is increased in the elderly. However, because of the toxicity of these medications, they should be used with caution, after less toxic alternatives have been considered and/or found ineffective. Recommended doses should not be exceeded, and the patient should be carefully monitored during therapy.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

{51}{85}
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For echothiophate or isoflurophate only
Physostigmine, ophthalmic{44}{49}{51}{62}    (use of this medication prior to echothiophate or isoflurophate may partially block the effects of the latter medications {44} and shorten their duration of action. {49} {62} Echothiophate and isoflurophate primarily inactivate pseudocholinesterase and incompletely inactivate acetylcholinesterase, {49} {62} whereas physostigmine and demecarium inactivate both pseudocholinesterase and acetylcholinesterase. {49} {62} Prior use of physostigmine inactivates the available acetylcholinesterase, thereby rendering it inaccessible to the incomplete inactivation by echothiophate or isoflurophate. {49} {62} This effect does not occur when physostigmine is given prior to demecarium, because both medications inactivate acetylcholinesterase, thereby producing an additive effect {49} {62})


For demecarium, echothiophate, or isoflurophate
Anesthetics, mucosal-local, ester-derivative, such as benzocaine, butacaine, butamben, and tetracaine or{39}
Anesthetics, parenteral-local, ester-derivative, such as chloroprocaine, procaine, propoxycaine, and tetracaine{43}{44}    (concurrent use with demecarium, echothiophate, or isoflurophate may inhibit the metabolism of these anesthetics, leading to prolonged anesthetic effect and increased risk of toxicity {39} {43} {51} {85})


» Anticholinergics or other medications with anticholinergic activity (see Appendix II ) or{02}{03}
» Antimyasthenics (see Appendix II ) or{02}{03}{04}{36}{43}{88}{89}{91}
» Cholinesterase inhibitors, other,{04}{44}{89}{91} possibly including topical malathion{51}{57}    (concurrent use of these medications with demecarium, echothiophate, or isoflurophate is not recommended except under strict medical supervision, because of the possibility of additive toxicity; {02} {03} {04} {44} {89} {91} caution may also be warranted with topical application of malathion if excessive quantities of it are used)


Belladonna alkaloids, ophthalmic or{49}{62}
Cyclopentolate or{49}{62}
Tropicamide{49}{61}{62}    (concurrent use of these parasympatholytics may antagonize the antiglaucoma and miotic actions of demecarium, echothiophate, or isoflurophate; {51} however, tropicamide is expected to have little effect, since it is short acting {61})


Carbamate- or organophosphate-type insecticides or pesticides{36}{43}    (exposure of patients using demecarium, echothiophate, or isoflurophate to these preparations may increase the possibility of systemic effects due to absorption of the insecticide or pesticide through the respiratory tract or skin; {02} {03} {04} {89} {91} patients should be advised to protect themselves from contact with such insecticides or pesticides during therapy with demecarium, echothiophate, or isoflurophate {02} {03} {04} {89} {91})


Cocaine{11}    (inhibition of cholinesterase activity by demecarium, echothiophate, or isoflurophate reduces or slows cocaine metabolism, thereby increasing and/or prolonging cocaine's effects and increasing the risk of toxicity; {11} cholinesterase inhibition may persist for weeks or months after demecarium, echothiophate, or isoflurophate has been discontinued {11})


Corticosteroids, ophthalmic{85}    (chronic or intensive use of ophthalmic corticosteroids may increase intraocular pressure and decrease the efficacy of the antiglaucoma agents {85})


Edrophonium{51}{78}{79}{80}{81}{82}    (caution is recommended in administering edrophonium to patients with symptoms of myasthenic weakness who are also using demecarium, echothiophate, or isoflurophate; symptoms of cholinergic crisis [overdosage] may be similar to those occurring with myasthenic crisis [underdosage] and the patient's condition may be worsened by use of edrophonium)


» Succinylcholine{02}{03}{04}{36}{39}{49}{62}{88}    (demecarium, echothiophate, or isoflurophate may decrease plasma concentrations or activity of pseudocholinesterase, the enzyme that metabolizes succinylcholine, {30} {60} {63} thereby enhancing the neuromuscular blockade of succinylcholine when it is used concurrently; {39} {44} cardiovascular collapse may occur; {03} {04} {39} {43} {44} {89} in addition, increased or prolonged respiratory depression or paralysis [apnea] may occur, {30} {43} {44} {89} which is of minor clinical significance while the patient is being mechanically ventilated; {51} however, caution and careful monitoring of the patient are recommended {91} during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively; {51} these effects may be more pronounced in pediatric patients; {89} {91} the effects of this interaction may persist for several weeks or months after demecarium, echothiophate, or isoflurophate has been discontinued)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Glaucoma, angle-closure, or predisposition to (except following iridectomy){02}{03}{04}{36}{43}{44}{88}{89}    (medication may increase the narrowing of the angle {44})


» Glaucoma associated with iridocyclitis{91} (anterior uveitis)    (medication may aggravate the inflammatory process {89} {91} and lead to the development of posterior synechiae {44})


» Sensitivity to the long-acting cholinergic antiglaucoma agent prescribed{02}{03}{04}{89}{91}
» Uveitis, active{91}    (medication may aggravate inflammation)


Risk-benefit should be considered when the following medical problems exist
» Asthma, bronchial{02}{03}{04}{36}{43}{44}{88}{89}{91}    (systemic absorption of medication may precipitate an attack {44} {53})


» Bradycardia and hypotension, pronounced{02}{03}{04}{43}{44}{88}{89}{91} or
» Epilepsy{02}{03}{04}{44}{88}{89}{91} or
» Gastrointestinal disturbances, spastic{02}{03}{04}{36}{44}{53}{88}{91} or
» Parkinsonism{02}{03}{04}{36}{44}{53}{88}{91} or
» Peptic ulcer{02}{03}{04}{44}{53}{88}{89}{91} or
» Urinary tract obstruction{36}{44}    (vagotonic effects of medication may worsen these conditions)


Down's syndrome (mongolism){44}    (echothiophate {44}, and possibly demecarium or isoflurophate, may cause hyperactivity in these children {44})


Hypertension, systemic{36}{43}{44} or
Hyperthyroidism{44}    (systemic absorption of medication may cause paradoxical exacerbation of these conditions {89} {91})


Iritis, quiescent or history of{02}{03}{36}{44}{88}{89}{91}    (medication may activate latent iritis {89} {91} and aggravate the inflammatory process {43})


Myasthenia gravis{02}{03}{04}{88}{89}{91}    (medication may cause additive effects with antimyasthenic agents)


» Myocardial infarction, recent{02}{03}{04}{36}{44}{88}    (vagotonic effects may worsen cardiac function; medication may increase risk of cardiac arrhythmias {89} {91})


» Retinal detachment, predisposition to or history of{02}{03}{04}{36}{43}{44}{50}{60}{63}{89}    (may result from drug-induced spasm of accommodation {43} {44})


Surgery, intraocular{67}{76}{85}{88}{91}    (intraocular surgery performed during the action of these medications may be complicated {76} {85} by hyphema {89} {91} and/or severe uveitis that is very difficult to manage; {67} {85} it is recommended that elective intraocular surgery not be performed {85} until the full duration of action of these medications has elapsed {67} {85} {91})


Uveitis, quiescent or history of{02}{03}{04}{43}{44}{88}{89}    (medication may activate latent uveitis and may predispose the patient to the development of posterior synechiae {43})


» Vagotonia, marked{02}{03}{04}{39}{44}{88}{89}{91}    (medication may increase vagotonic effects)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Gonioscopy    (recommended prior to, {44} {88} {89} {91} and soon after, {29} initiation of therapy {02} {03} {04} {49} {62})


Intraocular pressure determinations{44}{88}{91}    (recommended hourly for 3 or 4 hours initially {91}, then at periodic intervals during therapy {44})


Ophthalmologic examinations    (recommended initially with close patient observation during the first 24 hours of therapy {91}, then at periodic intervals {44} for patients on prolonged therapy, since formation of iris cysts [especially in children], {02} {03} {04} {88} conjunctival thickening, {02} {03} {04} {88} obstruction of nasolacrimal canals, {02} {03} {04} {88} retinal detachment, {02} {03} {04} {44} {50} {88} and lens opacities {02} {03} {04} {88} {89} may occur; also, the condition of the optic nerve should be monitored in patients with glaucoma {49} {62})




Side/Adverse Effects

Note: Lens opacities {02} {03} {04} {36} {43} {44} {60} {61} {63} and cataracts {61} may occur following prolonged use of echothiophate, isoflurophate, and possibly demecarium. {61} {66} {89} {91} While there is strong evidence implicating the phosphorylating medications, echothiophate and isoflurophate, there is little or no similar evidence implicating the carbamylating medication, demecarium. {61} {66} If lens opacities occur, they may {61} regress if therapy is discontinued early in their development; {44} {61} {66} however, once cataracts are established, they often continue developing despite cessation of therapy. {44} {61} {66} The incidence of cataracts appears to be directly related to the age of the patient and the concentration, frequency, and duration of the medication. {44} {61} {66}
Retinal detachment has been reported in a few patients during the use of ophthalmic long-acting cholinergic antiglaucoma agents, such as demecarium, echothiophate, or isoflurophate. {02} {03} {04} {36} {43} {44} {89} {91}
Repeated administration of demecarium, echothiophate, or isoflurophate may cause depression of the concentration of cholinesterase in the serum and erythrocytes, resulting in systemic effects. {02} {03} {04} {88} {89} {91}
Iris cysts, {02} {03} {04} {36} {43} {44} {60} {63} {88} {89} {91} conjunctival thickening, {02} {03} {04} {89} {91} and obstruction of nasolacrimal canals {02} {03} {04} may occur following prolonged {89} {91} use of demecarium, echothiophate, or isoflurophate, especially in children {89} {91}. If iris cysts occur and treatment with demecarium, echothiophate, or isoflurophate is continued, the cysts may enlarge and obscure the vision. {02} {03} {04} {44} {88} {91} In addition, rarely, the cysts may rupture or break free of the iris into the aqueous humor. {02} {03} {04} {44} {88} {89} {91} The cysts usually decrease in size following discontinuation of the medication. {02} {03} {04} {44} {88} {89} {91}
Activation of latent iritis or uveitis may occur following use of demecarium, echothiophate, or isoflurophate. {02} {03} {04} {44} {88} {89} {91}
A paradoxical increase in intraocular pressure may occur following use of demecarium, echothiophate, or isoflurophate. {02} {03} {04} {44} {89} {91} This may be alleviated by the use of a sympathomimetic, such as phenylephrine. {04} {89}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Burning, redness, stinging, or other irritation of eyes{02}{03}{04}{43}{44}{86}{87}{88}{89}{91}
    
eye pain{43}{44}{86}{87}
    
retinal detachment{39}{43}{88}{89}{91} (veil or curtain appearing across part of vision{01})

Symptoms of systemic absorption
    
Bradycardia{36}{43}{88}{91} (slow or irregular heartbeat{02}{03}{04}{36}{91})
    
bronchospasm{43}{44}{88} (shortness of breath, tightness in chest, or wheezing{02}{03}{04}{36})
    
hypotension, severe{02}{03}{43}{88} (unusual tiredness or weakness{02}{03})
    
increased sweating{02}{03}{04}{36}{43}{44}{88}{91}
    
loss of bladder control{02}{03}{04}{43}{88}{91}
    
muscle weakness{02}{03}{04}{36}{43}{88}
    
nausea,{02}{03}{04}{36}{43}{44}{60}{63}{88}{91} vomiting,{02}{03}{04}{36}{43}{44}{88}{91} diarrhea,{02}{03}{04}{36}{43}{44}{60}{63}{88}{91} or stomach cramps{02}{03}{36}{44}{60}{63}{88}{91} or pain{43}{44}
    
watering of mouth{02}{03}{04}{36}{43}{44}{88}{91}

Note: The most common systemic effects, especially in children, are nausea, vomiting, diarrhea, and stomach cramps or pain. {44}
Systemic absorption is rare with isoflurophate {43} {44} {88} because systemic absorption from ointment bases is minimal and the isoflurophate that is absorbed is hydrolyzed in the circulation almost immediately. {44}
Temporary discontinuation of the medication is recommended if symptoms of systemic absorption occur {89}.




Those indicating need for medical attention only if they continue or are bothersome
    
Accommodative myopia{02}{03}{36}{39}{43}{44}{88}{89}{91} (blurred vision or change in near or distance vision{02}{03}{04}{39}{43}{44})
    
browache{02}{03}{04}{36}{39}{43}{44}{88}{89}{91}
    
headache{02}{03}{39}{43}{88}{91}
    
miosis{36}{43} (difficulty in seeing at night or in dim light{36}{44}{60}{63})
    
twitching of eyelids{02}{03}{04}{43}{44}{88}{89}{91}
    
watering of eyes{02}{03}{04}{43}{44}{88}{89}{91}




Overdose
For specific information on the agents used in the management of ophthalmic long-acting cholinergic antiglaucoma agents overdose, see:
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Diazepam in Benzodiazepines (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
Clinical effects of overdose may occur as a result of systemic absorption following unintentional ingestion, or from topical application in the eye, or excessive skin contact with demecarium, echothiophate, or rarely, with isoflurophate. These effects may occur in addition to those symptoms and signs of systemic absorption. The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parenthesis where appropriate)—not necessarily inclusive:
    
Cardiac arrhythmias {91}
    
diarrhea {91}
    
muscle weakness {91}
    
profuse sweating {91}
    
respiratory difficulties {91}
    
shock {91}
    
urinary incontinence {91}


Treatment of overdose
Atropine sulfate injection {43} {88} {90} is used as an antidote to the systemic cholinergic effects of demecarium, echothiophate, or isoflurophate. {02} {03} {66}




For adults—Parenteral administration, intravenous if necessary, 0.4 to 0.6 mg or more {91}. The use of much larger doses of atropine in treating anticholinesterase intoxication in adults has been reported as follows: {91} intravenous, 2 to 6 {91} mg initially, then 2 mg repeated every hour, or more often {91}, until cholinergic symptoms disappear or signs of atropine toxicity appear. However, the risk of atropine intoxication increases when large doses are used, especially in sensitive individuals {91}.




For infants and {91} children younger than 12 years of age {91}—Intravenous or intramuscular, 0.01 mg per kilogram repeated every two hours as needed {91} until cholinergic symptoms disappear or signs of atropine toxicity appear. The maximum single dose should not exceed 0.4 mg {91}.

Intravenous pralidoxime chloride {02} {03} {36} {43} {88} {90} {91} (dose of 25 mg per kg of body weight [mg/kg]) {36} may be used as an adjunct to atropine therapy {02} {03} to reverse the muscle paralysis caused by nicotinic effects of demecarium, echothiophate, or isoflurophate. {44} The use of pralidoxime chloride for treating the systemic effects due to cholinesterase inhibitors is not intended to be a substitute for atropine therapy {91}.

A short-acting barbiturate {91} or diazepam {61} {62} {88} {90} may be administered for convulsions not controlled by atropine; {02} {03} {44} {88} {90} however, the dosage of the barbiturate should be adjusted to avoid central respiratory depression. {02} {03} {44} {88} {90} {91}

Artificial respiration {02} {03} {36} {44} {88} {90} {91} and maintenance of a clear airway {02} {03} {44} {88} {90} are indicated for severe weakness or paralysis of muscles of respiration. {02} {03} {44} {88} {90} {91}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Antiglaucoma Agents, Cholinergic, Long-acting (Ophthalmic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to demecarium, echothiophate, or isoflurophate

Pregnancy—Because of the toxicity of cholinesterase inhibitors in general, these medications are not recommended during pregnancy





Breast-feeding—Medications may be absorbed into the body and are not recommended during breast-feeding since they may cause adverse effects in nursing infants; a decision should be made whether to discontinue nursing or discontinue the medication





Use in children—The iris cysts that may occur following prolonged use of these medications occur frequently {85} in children; also, children may be more sensitive to the effects of these medications, especially if they are absorbed into the body

Other medications, especially anticholinergics or other medications with anticholinergic activity; antimyasthenics; or other cholinesterase inhibitors, possibly including topical malathion

Recent exposure to pesticides or insecticides
Other medical problems, especially active uveitis, angle-closure glaucoma or glaucoma associated with iridocyclitis, bronchial asthma, epilepsy, marked vagotonia, parkinsonism, peptic ulcer, predisposition to or history of retinal detachment, pronounced bradycardia or hypotension, recent myocardial infarction, spastic gastrointestinal disturbances, or urinary tract obstruction

Proper use of this medication
Proper administration technique for ophthalmic solution; removing excess solution around eye with clean tissue, being careful not to touch eye; washing hands immediately after application to avoid possible systemic absorption; {02} {03} {04} {89} {91} not touching applicator tip to any surface; keeping container tightly closed; applying the dose, or one of the two doses, at bedtime, since the solution may affect vision for several hours after administration {89} {91}

Proper administration technique for ophthalmic ointment; washing hands immediately after application to avoid possible systemic absorption; {02} {03} {04} not washing tip of ointment tube or allowing it to touch moist surface, since medication loses efficacy when exposed to moisture; not touching applicator tip to any surface, wiping tip of ointment tube with clean tissue; keeping container tightly closed; applying at bedtime, since ointment causes blurred vision after administration

» Importance of not using more medication than the amount prescribed

» Not using ocular solutions or ointment that may have become contaminated through improper handling or administration {89} {91}

» Proper dosing
Waiting 15 minutes after instilling preparations containing demecarium prior to inserting soft contact lenses {91}

Missed dose
If dosing schedule is—


• Every other day: Applying as soon as possible if remembered same day; if not remembered until the next day, applying it at that time, {61} then skipping a day; not doubling doses


• Once a day: Applying as soon as possible; if not remembered until next day, skipping missed dose and going back to regular dosing schedule; not doubling doses


• More than once a day: Applying as soon as possible; if almost time for next dose, skipping missed dose and going back to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician during therapy to check eye pressure and, for patients on prolonged therapy, to examine eyes

» Caution if any kind of surgery is required

» Caution if an ocular infection develops, or if ocular trauma occurs during therapy

» Caution in exposure to carbamate- or organophosphate-type insecticides or pesticides during therapy

» Making sure vision is clear before driving, using machines, or doing anything else that could be dangerous if not able to see well; caution because of possibility of decreased night vision, blurred vision or change in near or distance vision, or blurred vision for short time if using ointment


Side/adverse effects
Signs of potential side effects, especially burning, redness, stinging, or other irritation of the eyes; eye pain; retinal detachment; or symptoms of systemic absorption


General Dosing Information
To reduce the inconvenience of post-medication miosis, the daily dose or one of the daily doses of the medication may be administered at bedtime. {04} {89}

A stronger concentration may be required to produce adequate miosis and reduction in intraocular pressure in eyes with hazel or brown irides than in eyes with blue or light-colored irides {43} because miotics are less effective in heavily pigmented eyes. {43} {44}

During initial therapy, close observation of the patient and frequent (hourly) tonometric examinations are recommended to ensure that no immediate rise in intraocular pressure occurs {91}. Exams conducted at different times of the day will assist in the detection of inadequate control of intraocular pressure {89}.

To reduce the incidence of iris cyst formation, the frequency of administration should be minimal in all patients, especially in children. {02} {03} {91} In addition, the simultaneous administration of 2.5 {62} {63} to 10% {44} {61} ophthalmic phenylephrine with demecarium, echothiophate, or isoflurophate may prevent iris cyst formation. {43} {44} {60} {62} {63} However, phenylephrine will not prevent iris cysts if the phenylephrine is administered several hours before or after demecarium, echothiophate, or isoflurophate. {44} {62} The 2.5% concentration of phenylephrine appears to be as effective as the 10% concentration and causes less burning upon administration. {61} {62} {66}

Concurrent use of demecarium, echothiophate, {04} {89} or isoflurophate with epinephrine {04} {39} {44} {89}, a beta-adrenergic blocking agent, {29} {44} and/or a carbonic anhydrase inhibitor {04} {44} {89} results in additive effects, {04} {44} thereby providing better control of glaucoma. {04} {44} {89} Use of a reduced dose of demecarium, echothiophate, or isoflurophate may be possible. {44} A dosage reduction of the miotic medication (i.e., demecarium, echothiophate, or isoflurophate) results in the patient experiencing less miosis and/or accommodative {61} block. {44} In addition, concomitant administration of 2.5 to 10% {61} {66} ophthalmic phenylephrine or 1 or 2% ophthalmic epinephrine may improve the visual acuity of some patients by dilating the miotic eye without increasing the intraocular pressure. {44} {66}

Tolerance to demecarium, echothiophate, or isoflurophate may develop with prolonged use. {03} {04} {36} {44} {88} {89} Effectiveness may be restored by changing to another miotic for a short time and then resuming the original medication. {03} {04} {36} {44} {88} {89}

Following long-term use of these medications, dilation of blood vessels and resulting greater permeability will {67} {85} increase postoperative inflammation and may increase the risk of hyphema during ophthalmic surgery; {02} {03} {04} {43} {44} {50} {61} {62} {85} {89} {91} therefore, demecarium, echothiophate, or isoflurophate should be discontinued {02} {03} {43} {62} {85} {91} 2 to 3 weeks before eye surgery. {41} {43} {50} {85}

Temporary discontinuation of these medications is recommended if cardiac irregularities (e.g., arrhythmias) occur {89}.

For the solution dosage forms only
Although some manufacturers recommend a dose of 2 drops of an ophthalmic solution at appropriate intervals, the conjunctival sac usually will hold only 1 drop. {52} In addition, because of the potency of these medications and the possibility of systemic absorption, the smallest dose possible should be administered. {04}

To avoid excessive systemic absorption, patient should press finger to the lacrimal sac {02} {04} {39} {43} {89} {91} during and for 1 or 2 minutes following instillation of medication. {04} {89} {91}

DEMECARIUM

Summary of Differences
Precautions: Drug interactions and/or related problems—Physostigmine not listed as a precaution.


Ophthalmic Dosage Forms

DEMECARIUM BROMIDE OPHTHALMIC SOLUTION{61} USP

Usual adult and adolescent dose
Antiglaucoma agent (ophthalmic)
Topical, to the conjunctiva, 1 drop of a 0.125 or 0.25% solution one or two times a day. {90} {91}

Note: The usual dosage can vary from as much as 1 or 2 drops two times a day to as little as 1 or 2 drops two times a week. The 0.125% strength used twice a day usually results in optimal control of the diurnal variation in intraocular pressure, and is the preferred dosage for most open-angle glaucoma patients {91}.


Cyclostimulant (accommodative esotropia) {06} {61} {66}
Topical, to the conjunctiva, 1 drop of a 0.125 or 0.25% solution once a day for two or three weeks, then 1 drop every two days for three or four weeks, {02} {90} {91} at which time the patient's status should be reevaluated. {02} {90} {91} If improvement in the patient's clinical condition continues, the schedule may be reduced to 1 drop once a week, and eventually, to a trial without medication {91}.

Note: In the treatment of esotropia uncomplicated by amblyopia {91} or anisometropia, {61} {66} {91} the patient's condition should be evaluated every four to twelve weeks. {02} {91} It is recommended that therapy be discontinued after four months if a dosage of 1 drop every two days is still required to control condition. {02} {90}


Diagnostic aid (accommodative esotropia)
Topical, to the conjunctiva, 1 drop of a 0.125 or 0.25% solution once a day for two weeks, then 1 drop every two days for two or three weeks. {02} {90} {91}


Usual pediatric dose
Antiglaucoma agent (ophthalmic)
Cyclostimulant (accommodative esotropia) or
Diagnostic aid (accommodative esotropia)
For infants and young children: Use is not recommended.

Older children: See Usual adult and adolescent dose. {61} {66} {85} {90} {91}

Note: Clinicians differ as to the age at which children may receive this medication, their recommendations ranging from 12 months to 15 years. {85} Other clinicians feel that the lower end of the adult dose range, administered less frequently, may be used for infants and children. {85}



Strength(s) usually available
U.S.—


0.125% (Rx) [Humorsol{02}{90}{91} (benzalkonium chloride 1:5000) (sodium chloride)]


0.25% (Rx) [Humorsol{02}{90}{91} (benzalkonium chloride 1:5000) (sodium chloride)]

Note: The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients wearing soft contact lenses should wait at least 15 minutes after instilling eye drop solutions containing demecarium prior to inserting lenses {91}.


Canada—
Not commercially available {92}.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing or excessive heat.

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


ECHOTHIOPHATE


Ophthalmic Dosage Forms

ECHOTHIOPHATE IODIDE FOR OPHTHALMIC SOLUTION{61} USP

Usual adult and adolescent dose
Antiglaucoma agent (ophthalmic)
Topical, to the conjunctiva, 1 drop of a 0.03 to 0.25% solution one or two times a day. {04} {89}

Note: Twice-daily dosing provides optimal control of the diurnal variation in intraocular pressure {89}.
For conditions requiring higher strengths of the ophthalmic solution, a brief trial with the 0.03% solution is recommended {89}.


Cyclostimulant (accommodative esotropia)
Topical, to the conjunctiva, 1 drop of a 0.03 to 0.125% solution once a day or every two days. {04} {89}

Diagnostic aid (accommodative esotropia)
Topical, to the conjunctiva, 1 drop of a 0.125% solution once a day at bedtime for two or three weeks. {04} {89}


Usual pediatric dose
Antiglaucoma agent (ophthalmic)
Cyclostimulant (accommodative esotropia) or
Diagnostic aid (accommodative esotropia)
For infants and young children: Use is not recommended.

Older children: See Usual adult and adolescent dose. {66} {85} {89}

Note: Clinicians differ as to the age at which children may receive this medication, their recommendations ranging from 12 months to 15 years, with 2 years being the most frequently recommended age. {85} Other clinicians feel that the lower end of the adult dose range, administered less frequently, may be used for infants and children. {85}



Strength(s) usually available
U.S.—


0.03% (equivalent to 1.5 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{04}{89} (aluminum crimp seal is blue) (in powder—potassium acetate 40 mg) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—chlorobutanol 0.55%) (in diluent—mannitol 1.2%) (in diluent—boric acid 0.06%) (in diluent—sodium phosphate 0.026%)]


0.06% (equivalent to 3 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{04}{89} (aluminum crimp seal is red) (in powder—potassium acetate 40 mg) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—chlorobutanol 0.55%) (in diluent—mannitol 1.2%) (in diluent—boric acid 0.06%) (in diluent—sodium phosphate 0.026%)]


0.125% (equivalent to 6.25 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{04}{89} (aluminum crimp seal is green) (in powder—potassium acetate 40 mg) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—chlorobutanol 0.55%) (in diluent—mannitol 1.2%) (in diluent—boric acid 0.06%) (in diluent—sodium phosphate 0.026%)]


0.25% (equivalent to 12.5 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{04}{89} (aluminum crimp seal is yellow) (in powder—potassium acetate 40 mg) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—chlorobutanol 0.55%) (in diluent—mannitol 1.2%) (in diluent—boric acid 0.06%) (in diluent—sodium phosphate 0.026%)]

Canada—


0.06% (equivalent to 3 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{36} (in powder—potassium acetate) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—mannitol) (in diluent—hydrochloric acid) (in diluent—sodium phosphate)]


0.125% (equivalent to 6.25 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{36} (in powder—potassium acetate) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—mannitol) (in diluent—hydrochloric acid) (in diluent—sodium phosphate)]


0.25% (equivalent to 12.5 mg per 5 mL of sterile diluent) (Rx) [Phospholine Iodide{36} (in powder—potassium acetate) (in powder—sodium hydroxide) (in powder—acetic acid) (in diluent—mannitol) (in diluent—hydrochloric acid) (in diluent—sodium phosphate)]

Packaging and storage:
Prior to reconstitution, store under refrigeration between 2 and 8 °C (36 and 46 °F). Reconstituted product may be stored between 15 and 30 °C (59 and 86 °F). Store in a tight container. Protect the reconstituted solution from freezing.

Preparation of dosage form:
For reconstitution of echothiophate iodide powder, use only the diluent supplied by the manufacturer to provide for optimum stability. Use aseptic technique. {89}

Stability:
Reconstituted solution is stable for about 3 to 4 weeks {04} {36} {89} at room temperature or for 3 to 6 months {04} {36} {89} if refrigerated, depending on the manufacturer.

Auxiliary labeling:
   • For the eye.
   • Beyond-use date. {04}
   • Keep container tightly closed.


ISOFLUROPHATE


Ophthalmic Dosage Forms

Note: Because isoflurophate is not commercially available in the U.S. or Canada, the bracketed uses and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.


ISOFLUROPHATE OPHTHALMIC OINTMENT{61} USP

Usual adult and adolescent dose
[Antiglaucoma agent (ophthalmic)]1
Topical, to the conjunctiva, a thin strip (approximately 0.5 cm) of a 0.025% ointment once every three days to three times a day. {03} {43} {88}

[Cyclostimulant (accommodative esotropia)]1{06} {61} {66}
Topical, to the conjunctiva, a thin strip (approximately 0.5 cm) of a 0.025% ointment once a day at bedtime for two weeks, {88} then once a week to once every two days, depending on the patient's condition, for two months. {03} {06} {88}

Note: In the treatment of esotropia uncomplicated by anisometropia, {61} {66} it is recommended that therapy be discontinued if the patient's condition cannot be maintained on a dosage interval of at least every two days. {03} {88}


[Diagnostic aid (accommodative esotropia)]1
Topical, to the conjunctiva, a thin strip (approximately 0.5 cm) of a 0.025% ointment once a day at bedtime for two weeks. {03} {88}


Usual pediatric dose
[Antiglaucoma agent (ophthalmic)]1
[Cyclostimulant (accommodative esotropia) or]1
[Diagnostic aid (accommodative esotropia)]1
For infants and young children: Use is not recommended.

Older children: See Usual adult and adolescent dose. {66} {85} {88}

Note: Clinicians differ as to the age at which children may receive this medication, their recommendations ranging from 12 months to 15 years, with 2 years being the most frequently recommended age. {85} Other clinicians feel that the lower end of the adult dose range, administered less frequently, may be used for infants and children. {85}



Strength(s) usually available
U.S.—
Not commercially available {93}.

Canada—
Not commercially available {93}.

France—


[Diflupyl{93}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
Isoflurophate hydrolyzes in the presence of water to form hydrofluoric acid and becomes inactivated. {03} {88}

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.



Revised: 06/15/99



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