Ophthalmic drugs in pregnancy and lactation

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.

A number of drugs are available for ophthalmic use. This review focuses on single drug products and, although combination drug products are not discussed, these formulations typically include the drugs reviewed here.

Since it appears that ophthalmic medications are commonly used for a wide range of conditions and ages, one would expect to see numerous reports of their use in the eyes of pregnant or breastfeeding patients. Unfortunately, the opposite is true. The majority of the drugs have no human pregnancy or lactation data. When there are human data, it invariably involves the systemic use of the drug for other indications, rather than its ophthalmic use. Moreover, the animal reproduction data are usually not relevant because they involve systemic drugs (e.g., IV or oral). Consequently, determining the level of risk an ophthalmic drug presents to an embryo and/or fetus is primarily based on time and dose, the two cardinal principles of teratology.

Avoiding exposure during organogenesis – the period when a drug can cause developmental toxicity (altered growth, structural anomalies, functional and/or behavioral deficits, or death) – is usually best, but may not be possible in some cases, including glaucoma, eye infections, and eye surgery. Fortunately, the systemic concentrations of drugs applied topically to the eye are typically thought to be low, even though the levels of most drugs have not been studied. Thus, the risk to the embryo and/or fetus in most cases can be considered low and the drug classified as compatible in pregnancy and breastfeeding.

If a topical eye drug must be used during pregnancy or lactation, teach the patient how to decrease the amount of drug reaching the systemic circulation. This involves placing pressure over the tear duct in the corner of the eye for 1 minute or more, then removing any excess solution with absorbent tissue.

In the sections below, drugs are shown by indication or by pharmacologic class. The term “human eye data” refers to the use of the drug in pregnancy and/or lactation.

Glaucoma

If you are caring for a pregnant patient who is being treated for glaucoma, two recent reviews may be helpful: Surv Ophthalmol. 2011 Jul-Aug;56(4):324-35 and Curr Opin Ophthalmol. 2014 Mar;25(2):93-7.

Sympathomimetics (alpha-adrenergic agonists) include apraclonidine (Iopidine), which has no human eye data, and brimonidine (Alphagan P), which has one case report in pregnancy and breastfeeding showing no fetal or nursing infant harm.

Four of the five beta-adrenergic blockers have no human eye data: betaxolol (Betoptic), carteolol (Ocupress), levobunolol (Betagan), and metipranolol, but there are two case reports for timolol (Betimol, Istalol, Timoptic, Timoptic-XE) showing no fetal harm in one newborn and growth restriction in the other.

Among the miotics, there are limited human eye data for pilocarpine (Isopto Carpine) and no fetal harm was observed. For echothiophate iodide (Phospholine Iodide), there is one case report of a normal full-term infant whose mother was treated with the agent up to 32 weeks’ gestation and then with pilocarpine for 8 weeks (Arch Ophthalmol. 1968 Mar;79[3]:283-5).

Fuse/Thinkstock.com

Carbonic anhydrase inhibitors include brinzolamide (Azopt), which has no human eye data, and dorzolamide (Trusopt), which has growth restriction in one case treated with fixed combination of dorzolamide and timolol. There are no human eye data for unoprostone isopropyl (Rescula), a synthetic docosanoid.

Of the four prostaglandin analogs, three have no human eye data, bimatoprost (Lumigan), tafluprost (Zioptan), and travoprost (Travatan Z). There were 11 pregnancies exposed to latanoprost (Xalatan). The outcomes of these cases were one lost to follow-up, one miscarriage, and nine infants without congenital anomalies (Am J Ophthalmol. 2004 Aug;138[2]:305-6).

Mitomycin (Mitosol) is an antimetabolite that is given topically to the surgical site of glaucoma filtration surgery. No reports of its use in pregnant humans have been located. According to the manufacturer, clinically significant systemic concentrations are not expected.

Antiseptics

Povidone-iodine (Betadine) is indicated for prepping of the periocular region. There does not appear to be any risk to the embryo-fetus or nursing infant from this indication.

Antihistamines

The four ophthalmic agents in this class are alcaftadine (Lastacaft), azelastine (Optivar), emedastine (Emadine), and epinastine (Elestat). There are no human eye data for these agents but, like antihistamines given systemically, they are probably compatible in pregnancy and lactation.

Antihistamine-mast cell stabilizers

There are no human eye data for bepotastine (Bepreve), ketotifen (Alaway), and olopatadine (Pataday, Patanol). Peak plasma concentrations of bepotastine were 5.1-7.3 ng/mL for 1-2 hours after instillation and were less than 2 ng/mL at 24 hours. It appears that these drugs can also be classified as compatible in pregnancy and lactation.

Anti-infectives

Ten anti-infectives are available for topical treatment of eye infections (systemic concentrations if known): besifloxacin (Besivance) (0.43 ng/mL), ciprofloxacin (less than 2.5 ng/mL), gentamicin, gatifloxacin (Zymaxid) (less than 5 ng/mL), levofloxacin (Iquix) (10.9 ng/mL), moxifloxacin (Vigamox) (2.7 ng/mL), ofloxacin (1.9 ng/mL), sulfacetamide (Isopto Cetamide), and tobramycin. The tenth agent, natamycin (Natacyn), is an antifungal. According to the manufacturer, systemic absorption is not expected.

None of these agents have human eye data, but they are usually considered compatible in pregnancy and breastfeeding when systemic formulations are used, so they should be compatible when used in the eye.

Antivirals

Ganciclovir (Zirgan) has no human eye data but, according to the manufacturer, the daily ophthalmic dose is about 0.04% and 0.1% of the oral and IV doses, respectively. Thus, minimal systemic exposure is expected. Trifluridine (Viroptic) also has no eye human data. As reported in the product information, detectable blood concentrations of the drug were not found in healthy normal subjects indicating that systemic absorption was negligible.

Corticosteroids

Among the nine corticosteroid products, six are suspensions or ointments, one is an injection, and two are implants. In most nonpregnant patients receiving the dexamethasone (Ozurdex) intravitreal implant, plasma dexamethasone concentrations were undetectable (less than 50 pg/mL) but, in some, ranged from 52 pg/mL to 102 pg/mL. There is only one case report describing the use of topical dexamethasone suspension (Maxidex) in pregnancy. In that case, dexamethasone and clindamycin were given in the first and second trimesters and the woman eventually gave birth to a normal full term infant (Int Ophthalmol. 1998-1999;22[2]:85-8).

For the fluocinolone (Retisert) ocular implant, systemic absorption of detectable amounts of the drug have not been observed. In a second report, a patient who had type 1 diabetes and was 6 months pregnant received a 2-mg intravitreal injection of triamcinolone (Triesence) in both eyes. No adverse effects in the mother or fetus were noted (Clin Ophthalmol. 2011;5:439-41).

There are no human eye data for five topical corticosteroids: difluprednate (Durezol), fluorometholone (Flarex, Fluor-OP, FML), loteprednol (Alrex, Lotemax), prednisolone (Econopred), and rimexolone (Vexol). Only two of the five drugs had information about systemic absorption. For difluprednate, blood levels were below the quantification limit (50 ng/mL). Extremely low levels were detected after the use of rimexolone with a mean serum concentration of 130 pg/mL (range less than 80-470 pg/mL).

Cycloplegics-mydriatics

This class includes four anticholinergic agents: atropine, cyclopentolate (Cyclogyl), homatropine, and tropicamide (Mydriacyl). Systemic absorption has not been studied for these drugs and there are no reports of their use in pregnancy or lactation.

Cystine-depleting agents

There are no reports describing the use of cysteamine (Cystaran) in human pregnancy or lactation. Since the drug is given as one drop in each eye every waking hour, transfer to the systemic circulation should be expected, but the amount, if it occurs, has not been reported.

Immunologics

There are no reports on the use of cyclosporine (Restasis) eye drops in human pregnancy or during breastfeeding. However, data for the systemic use of the drug during these conditions has shown it to be low risk. After long term ophthalmic use, blood concentrations of the drug were below the quantitation limit of 0.1 ng/mL.

Local anesthetics

The three drugs in this class are lidocaine, proparacaine (Alcaine), and tetracaine (Altacaine, Tetravisc). There is no information regarding the use of these agents in pregnancy or lactation. Since they are used for brief periods, the risk to an embryo or nursing infant appears to be nil.

Mast cell stabilizers

There are three drugs in this class that can be used topically in the eye: cromolyn, lodoxamide (Alomide), and nedocromil (Alocril). There are no human eye data for these agents. Systemic concentrations of lodoxamide were below the detection limit of 2.5 ng/mL.

Miotics

The two miotics are acetylcholine (Miochol E) and carbachol (Carbastat, Miostat). Both are used immediately before eye surgery. The amount, if any, in the systemic circulation is unknown. No reports of human eye use in pregnancy or lactation have been found.

NSAIDs

The five drugs in this class are bromfenac (Xibrom), diclofenac (Voltaren), flurbiprofen (Ocufen), ketorolac, and nepafenac (Nevanac). Although it has not been studied, the estimated plasma level for bromfenac is less than 50 ng/mL. For diclofenac, the plasma concentration was below the limit of quantification (10 ng/mL). In a study conducted with ketorolac, only 5 of 26 subjects had detectable plasma concentrations (10.7 to 22.5 ng/mL). These levels were about 2% of the peak plasma levels after oral dosing. For nepafenac, the peak plasma concentrations of the parent drug and active metabolite were 0.3 and 0.4 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant are nil.

Photodynamic therapy

Verteporfin (Visudyne) is given intravenously. Three reports have described its use in three pregnancies. In all cases, the infants were healthy at birth and had normal growth (Acta Ophthalmol Scand. 2004 Oct;82[5]:623-4, Eye [Lond]. 2009 Jun;23[6]:1479, and Aust N Z J Obstet Gynaecol. 2009 Apr;49[2]:236-7).

Proteolytic enzymes

No human eye data were found for ocriplasmin (Jetrea), an agent given as an intravitreal injection. Although it was not studied, detectable levels of the drug in the systemic circulation are not expected, according to the manufacturer.

Selective vascular endothelial growth factor antagonists

There are three agents in this class: aflibercept (Eylea), pegaptanib (Macugen), and ranibizumab (Lucentis). There are no human eye data for these drugs. All are given as intravitreal injection. The systemic concentrations of the three drugs were a mean 0.02 mcg/mL; 80 ng/mL (after a dose of 10 times the recommended dose); and an estimated minimum 0.22 ng/mL, respectively. These data suggest that the risk to the embryo-fetus or a nursing infant is nil.

Sympathomimetics (decongestants)

There are four ophthalmic agents in this class and none have human eye data. Naphazoline (Naphcon, Vasocon) is the only one of the four that requires a prescription. No reports describing the systemic absorption, if any, have been found. The other three agents are available over the counter. They are oxymetazoline (Visine L.R.), phenylephrine, and tetrahydrozoline (Opti-Clear). Although the amount reaching the systemic circulation was not provided by the manufacturers for these three agents, a caution was placed on phenylephrine stating that systemic absorption, although rare, might cause alpha-adrenergic effects, such as a rise in blood pressure and reflex atropine-sensitive bradycardia.

The risk to the embryo-fetus or nursing infant from ophthalmic drugs appears to be low, with the possible exception of phenylephrine. Nevertheless, if any of these agents are used in pregnancy or during breastfeeding, careful assessment of the embryo-fetus and nursing infant should be conducted. Moreover, research on the potential effects of ophthalmic drugs on the embryo-fetus and nursing infant are desperately needed.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.