DURYSTA® (bimatoprost intracameral implant) is indicated for the reduction of intraocular pressure (IOP) in patients with open angle glaucoma (OAG) or ocular hypertension (OHT).

{ "type": "p", "children": [], "text": "DURYSTA® (bimatoprost intracameral implant) is indicated for the reduction of intraocular pressure (IOP) in patients with open angle glaucoma (OAG) or ocular hypertension (OHT)." }

DURYSTA is an ophthalmic drug delivery system for a single intracameral administration of a biodegradable implant. DURYSTA should not be readministered to an eye that received a prior DURYSTA.  

The intracameral injection procedure must be performed under magnification that allows clear visualization of the anterior chamber structures and should be carried out using standard aseptic conditions for intracameral procedures, with the patient’s head in a stabilized position. The eye should not be dilated prior to the procedure.

Remove the foil pouch from the carton and examine for damage. Then, open the foil pouch over a sterile field and gently drop the applicator on a sterile tray. Once the foil pouch is opened, use the applicator promptly.

Figure 1

Perform a detailed visual inspection of the applicator, including ensuring that the actuator button has not been depressed, and the safety tab is in place. Carefully remove the plastic safety cap taking care to avoid contacting the needle tip. Inspect the needle tip for damage under magnification prior to use; the implant retention plug may be visible in the bevel and should not be removed.

Prior to use, remove the safety tab by pulling it out perpendicular to the long axis of the applicator (refer to Figure 1a above). Do not twist or bend the tab.

Stabilize the eye as the needle is advanced through the cornea. Enter the anterior chamber with the needle bevel visible through clear cornea. Enter parallel to the iris plane, adjacent to the limbus through clear cornea in the superotemporal quadrant.

The needle should be inserted approximately 2 bevel lengths with the bevel completely within the anterior chamber; avoid positioning the needle bevel directly over the pupil. Ensure the needle is not bent before depressing the actuator button. See Figure 2.

Figure 2

Depress the back half of the actuator button (refer to Figure 1b above) firmly until an audible and/or palpable click is noted.

Following the release of the implant, remove the needle via the same track in which it was inserted and tamponade the opening. The implant should not be left in the corneal injection track.

Check the injection site for leaks; make sure that it is self-sealing and the anterior chamber is formed.

After injection, do not recap the needle. Dispose of the used applicator in a sharps disposal container and in accordance with local requirements.

Instruct the patient to remain upright for at least 1 hour after the procedure so the implant can settle.

Some degree of eye redness and discomfort is expected following administration. However, it is recommended to instruct patients that if the eye becomes progressively red, sensitive to light, painful, or develops a change in vision, they should immediately contact the physician.

Intracameral implant containing 10 mcg of bimatoprost in a drug delivery system.

{ "type": "p", "children": [], "text": "Intracameral implant containing 10 mcg of bimatoprost in a drug delivery system." }

DURYSTA is contraindicated in patients with active or suspected ocular or periocular infections.

DURYSTA is contraindicated in patients with corneal endothelial cell dystrophy (e.g., Fuchs’ Dystrophy) [see Warnings and Precautions (5.1)].

DURYSTA is contraindicated in patients with prior corneal transplantation, or endothelial cell transplants [e.g., Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK)].

DURYSTA is contraindicated in patients whose posterior lens capsule is absent or ruptured, due to the risk of implant migration into the posterior segment. Laser posterior capsulotomy in pseudophakic patients is not a contraindication for DURYSTA use if the intraocular lens fully covers the opening in the posterior capsule.

DURYSTA is contraindicated in patients with hypersensitivity to bimatoprost or to any other components of the product [see Adverse Reactions (6.1)].

The presence of DURYSTA implants has been associated with corneal adverse reactions and increased risk of corneal endothelial cell loss. Administration of DURYSTA should be limited to a single implant per eye without retreatment. Caution should be used when prescribing DURYSTA in patients with limited corneal endothelial cell reserve.

Following administration with DURYSTA, the intracameral implant is intended to settle within the inferior angle. DURYSTA should be used with caution in patients with narrow iridocorneal angles (Shaffer grade ˂ 3) or anatomical obstruction (e.g., scarring) that may prohibit settling in the inferior angle.

Macular edema, including cystoid macular edema, has been reported during treatment with ophthalmic bimatoprost, including DURYSTA intracameral implant. DURYSTA should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

Prostaglandin analogs, including DURYSTA, have been reported to cause intraocular inflammation. DURYSTA should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.

Ophthalmic bimatoprost, including DURYSTA intracameral implant, has been reported to cause changes to pigmented tissues, such as increased pigmentation of the iris. Pigmentation of the iris is likely to be permanent. Patients who receive treatment should be informed of the possibility of increased pigmentation. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. While treatment with DURYSTA can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

Intraocular surgical procedures and injections, including DURYSTA, have been associated with endophthalmitis. Proper aseptic technique must always be used with administering DURYSTA, and patients should be monitored following the administration.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common ocular adverse reaction observed in two randomized, active-controlled clinical trials with DURYSTA in patients with OAG or OHT was conjunctival hyperemia, which was reported in 27% of patients. Other common ocular adverse reactions reported in 5-10% of patients were foreign body sensation, eye pain, photophobia, conjunctival hemorrhage, dry eye, eye irritation, intraocular pressure increased, corneal endothelial cell loss, vision blurred, and iritis. Ocular adverse reactions occurring in 1-5% of patients were anterior chamber cell, lacrimation increased, corneal edema, aqueous humor leakage, iris adhesions, ocular discomfort, corneal touch, iris hyperpigmentation, anterior chamber flare, anterior chamber inflammation, and macular edema. The following additional adverse drug reactions occurred in less than 1% of patients: hyphema, iridocyclitis, uveitis, corneal opacity, corneal thickening, product administered at inappropriate site, corneal decompensation, cystoid macular edema, and drug hypersensitivity.

The most common nonocular adverse reaction was headache, which was observed in 5% of patients.

The following adverse reactions have been identified during postapproval use of DURYSTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye disorders: endophthalmitis

Risk Summary

There are no adequate and well-controlled studies of DURYSTA (bimatoprost intracameral implant) administration in pregnant women to inform a drug associated risk. Oral administration of bimatoprost to pregnant rats and mice throughout organogenesis did not produce adverse maternal or fetal effects at clinically relevant exposures. Oral administration of bimatoprost to rats from the start of organogenesis to the end of lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant exposures [see Animal Data]. 

Data

Animal Data

In an embryofetal development rat study, oral administration of bimatoprost to pregnant rats during organogenesis produced abortion at 0.6 mg/kg/day (1770-times the human systemic exposure to bimatoprost from DURYSTA, based on Cmax and a blood-to plasma partition ratio of 0.858). The No Observed Adverse Effect Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 470-times the human systemic exposure to bimatoprost from DURYSTA, based on Cmax). No fetal abnormalities were observed at doses up to 0.6 mg/kg/day.

In an embryofetal development mouse study, oral administration of bimatoprost to pregnant mice during organogenesis produced abortion and early delivery at 0.3 mg/kg/day (2240-times the human systemic exposure to bimatoprost from DURYSTA, based on plasma Cmax level; blood-to plasma partition ratio of 0.858). The NOAEL for abortion and early delivery was 0.1 mg/kg/day (400-times the human systemic exposure to bimatoprost from DURYSTA, based on Cmax). No fetal abnormalities were observed at doses up to 0.6 mg/kg/day (5200-times the human systemic exposure to bimatoprost from DURYSTA, based on Cmax).

In a pre/postnatal development study, oral administration of bimatoprost to pregnant rats from gestation day 7 through lactation resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, and reduced pup body weight at 0.3 mg/kg/day (estimated 470-times the human systemic exposure to bimatoprost from DURYSTA, based plasma Cmax and a blood-to plasma partition ratio of 0.858). No adverse effects were observed in rat offspring at 0.1 mg/kg/day (estimated 350-times the human systemic exposure to bimatoprost from DURYSTA, based on plasma Cmax).

Risk Summary

There is no information regarding the presence of bimatoprost in human milk, the effects on the breastfed infants, or the effects on milk production. In animal studies, topical bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when DURYSTA is administered to a nursing woman.

The developmental and health benefits of breastfeeding should be considered, along with the mother's clinical need for DURYSTA and any potential adverse effects on the breastfed child from DURYSTA.

Safety and effectiveness of DURYSTA in pediatric patients have not been established.

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

DURYSTA is a sterile intracameral implant containing 10 mcg of bimatoprost, a prostaglandin analog, in a solid polymer sustained-release drug delivery system (DDS). The drug delivery system consists of poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (D,L-lactide) acid end, and polyethylene glycol 3350. DURYSTA is preloaded into a single-use, DDS applicator to facilitate injection of the rod-shaped implant directly into the anterior chamber of the eye. The chemical name for bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-N-ethyl-5-heptenamide, and its molecular weight is 415.57. Its molecular formula is C25H37NO4. Its structural formula is:

{ "type": "p", "children": [], "text": "DURYSTA is a sterile intracameral implant containing 10 mcg of bimatoprost, a prostaglandin analog, in a solid polymer sustained-release drug delivery system (DDS). The drug delivery system consists of poly (D,L-lactide), poly (D,L-lactide-co-glycolide), poly (D,L-lactide) acid end, and polyethylene glycol 3350. DURYSTA is preloaded into a single-use, DDS applicator to facilitate injection of the rod-shaped implant directly into the anterior chamber of the eye. The chemical name for bimatoprost is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-N-ethyl-5-heptenamide, and its molecular weight is 415.57. Its molecular formula is C25H37NO4. Its structural formula is:" }

Bimatoprost is a white to off-white powder, soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. The polymer matrix slowly degrades to lactic acid and glycolic acid.

{ "type": "p", "children": [], "text": "Bimatoprost is a white to off-white powder, soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. The polymer matrix slowly degrades to lactic acid and glycolic acid." }

Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. Bimatoprost is believed to lower IOP in humans by increasing outflow of aqueous humor through both the trabecular meshwork (conventional) and uveoscleral routes (unconventional). Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

After a single administration of DURYSTA, bimatoprost concentrations were below the lower limit of quantitation (0.001 ng/mL) in the majority (approximately 92%) of patients. The maximum bimatoprost concentration observed in any patient was 0.00224 ng/mL. Bimatoprost acid concentrations were also below the lower limit of quantitation (0.01 ng/mL) in almost all (approximately 99%) of patients.

Carcinogenesis

Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses up to 2 mg/kg/day and 1 mg/kg/day respectively for 104 weeks (approximately 3100 and 1700 times, respectively, the maximum human exposure [based on plasma Cmax levels; blood-to-plasma partition ratio of 0.858]).

Mutagenesis

Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.

Impairment of Fertility

Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (1770-times the maximum human exposure, based on plasma Cmax; blood-to-plasma partition ratio of 0.858).

Efficacy was evaluated in two multicenter, randomized, parallel-group, controlled 20-month (including 8-month extended follow-up) studies of DURYSTA compared to twice daily topical timolol 0.5% drops, in patients with OAG or OHT. DURYSTA demonstrated an IOP reduction of approximately 5-8 mmHg in patients with a mean baseline IOP of 24.5 mmHg (see Figures 3 and 4).

{ "type": "p", "children": [], "text": "Efficacy was evaluated in two multicenter, randomized, parallel-group, controlled 20-month (including 8-month extended follow-up) studies of DURYSTA compared to twice daily topical timolol 0.5% drops, in patients with OAG or OHT. DURYSTA demonstrated an IOP reduction of approximately 5-8 mmHg in patients with a mean baseline IOP of 24.5 mmHg (see Figures 3 and 4)." }

Figure 3: Study 1 Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP

{ "type": "p", "children": [], "text": "\nFigure 3: Study 1 Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP\n" }

Figure 4: Study 2 Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP

{ "type": "p", "children": [], "text": "\nFigure 4: Study 2 Mean IOP (mmHg) by Treatment Group and Treatment Difference in Mean IOP\n" }

DURYSTA contains a 10 mcg bimatoprost intracameral implant in a single-use applicator that is packaged in a sealed foil pouch containing desiccant, NDC 0023-9652-01.

{ "type": "p", "children": [], "text": "DURYSTA contains a 10 mcg bimatoprost intracameral implant in a single-use applicator that is packaged in a sealed foil pouch containing desiccant, NDC 0023-9652-01. " }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store refrigerated at 2°C to 8°C (36°F to 46°F).

{ "type": "p", "children": [], "text": "Store refrigerated at 2°C to 8°C (36°F to 46°F)." }

Treatment-related Effects 

{ "type": "p", "children": [], "text": "\nTreatment-related Effects \n" }

Advise patients about the potential risk for complications including, but not limited to, the development of corneal adverse events, intraocular inflammation or endophthalmitis [see Warnings and Precautions (5.1, 5.4, 5.6)].

{ "type": "p", "children": [], "text": "Advise patients about the potential risk for complications including, but not limited to, the development of corneal adverse events, intraocular inflammation or endophthalmitis [see Warnings and Precautions (5.1, 5.4, 5.6)]. " }

Potential for Pigmentation 

{ "type": "p", "children": [], "text": "\nPotential for Pigmentation \n" }

Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent [see Warnings and Precautions (5.5)]. " }

When to Seek Physician Advice 

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Advise patients that if the eye becomes red, sensitive to light, painful, or develops a change in vision, they should seek immediate care from an ophthalmologist [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Advise patients that if the eye becomes red, sensitive to light, painful, or develops a change in vision, they should seek immediate care from an ophthalmologist [see Warnings and Precautions (5.6)]." }

Distributed by: AbbVie Inc. North Chicago, IL 60064

{ "type": "p", "children": [], "text": "Distributed by: AbbVie Inc. North Chicago, IL 60064" }

© 2024 AbbVie. All rights reserved. DURYSTA and its design are trademarks of Allergan, Inc., an AbbVie company.

{ "type": "p", "children": [], "text": "© 2024 AbbVie. All rights reserved. DURYSTA and its design are trademarks of Allergan, Inc., an AbbVie company." }

V2.0USPI9652

{ "type": "p", "children": [], "text": "V2.0USPI9652" }

NDC 0023-9652-01DURYSTA® (bimatoprost intracameral implant) 10 mcgOne Sterile, Single-Dose ApplicatorFor Intracameral administrationRx only

{ "type": "p", "children": [], "text": "NDC 0023-9652-01DURYSTA® (bimatoprost intracameral implant) 10 mcgOne Sterile, Single-Dose ApplicatorFor Intracameral administrationRx only" }

Bimatoprost ophthalmic solution 0.03% is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.

The recommended dosage is one drop in the affected eye(s) once daily in the evening. Bimatoprost ophthalmic solution 0.03% should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect.

Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours.

Bimatoprost ophthalmic solution 0.03% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.

Ophthalmic solution containing bimatoprost 0.3 mg/mL

Bimatoprost ophthalmic solution 0.03% is contraindicated in patients with hypersensitivity to bimatoprost or to any of the ingredients [see Adverse Reactions (6.2)].

Bimatoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as bimatoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of bimatoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known.

Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with bimatoprost ophthalmic solution 0.03% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

Bimatoprost ophthalmic solution 0.03% may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment.

Prostaglandin analogs, including bimatoprost, have been reported to cause intraocular inflammation. In addition, because these products may exacerbate inflammation, caution should be used in patients with active intraocular inflammation (e.g., uveitis).

Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. Bimatoprost ophthalmic solution 0.03% should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Bimatoprost ophthalmic solution 0.03% contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact lenses. Contact lenses should be removed prior to instillation of bimatoprost ophthalmic solution 0.03% and may be reinserted 15 minutes following its administration.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, the most frequent events associated with the use of bimatoprost ophthalmic solution 0.03% occurring in approximately 15% to 45% of patients, in descending order of incidence, included conjunctival hyperemia, growth of eyelashes, and ocular pruritus. Approximately 3% of patients discontinued therapy due to conjunctival hyperemia.

Ocular adverse events occurring in approximately 3 to 10% of patients, in descending order of incidence, included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening. The following ocular adverse events reported in approximately 1 to 3% of patients, in descending order of incidence, included: eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. In less than 1% of patients, intraocular inflammation was reported as iritis.

Systemic adverse events reported in approximately 10% of patients were infections (primarily colds and upper respiratory tract infections). The following systemic adverse events reported in approximately 1 to 5% of patients, in descending order of incidence, included headaches, abnormal liver function tests, asthenia and hirsutism.

The following adverse reactions have been identified during postapproval use of bimatoprost ophthalmic solution 0.03%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to bimatoprost ophthalmic solution, or a combination of these factors, include: abnormal hair growth, asthma-like symptoms, dizziness, dyspnea, eyelid edema, hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis, hypertension, nausea, and periorbital and lid changes associated with periorbital fat atrophy leading to skin tightness, deepening of the eyelid sulcus, eyelid ptosis, enophthalmos and eyelid retraction; and skin discoloration (non-periocular).

Risk Summary

There are no adequate and well-controlled studies of bimatoprost ophthalmic solution 0.03% administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based on bimatoprost postmarketing experience.

In embryofetal developmental studies, administration of bimatoprost in pregnant mice and rats during organogensis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the human exposure at the recommended clinical dose (based on blood area under the curve [AUC] levels). These adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure at the recommended clinical dose.

In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality at oral doses at least 41 times the human systemic exposure at the recommended clinical dose (based on blood AUC levels). No adverse effects were observed in rat offspring at exposures estimated at 14 times the human exposure at the recommended clinical dose (based on blood AUC levels).

Because animal reproductive studies are not always predictive of human response bimatoprost ophthalmic solution 0.03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

In an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure at the recommended human ophthalmic dose [RHOD], based on AUC). The No Observed Adverse Effect Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 47 times the human systemic exposure at the RHOD, based on AUC). No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day.

In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times the human systemic exposure at the RHOD, based on AUC). The NOAEL for abortion and early delivery was 0.1 mg/kg/day (2.6 times the human systemic exposure at the RHOD, based on AUC). No abnormalities were observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure at the RHOD, based on AUC).

In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from    gestation day 7 to lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were observed at exposures at least 41 times the human systemic exposure at the RHOD, based on AUC. The NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated at 14 times the human systemic exposure at the RHOD, based on AUC).

Risk Summary

It is not known whether topical ocular treatment with bimatoprost ophthalmic solution 0.03% could result in sufficient systemic absorption to produce detectable quantities in human milk. In animal studies, bimatoprost has been shown to be present in breast milk of lactating rats at an intravenous dose (i.e., 1 mg/kg) 324 times the RHOD (on a m2g/m basis), however no animal data is available at clinically relevant doses.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for bimatoprost ophthalmic solution 0.03% and any potential adverse effects on the breastfed child from bimatoprost ophthalmic solution 0.03%.

Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

No information is available on overdosage in humans. If overdose with bimatoprost ophthalmic solution 0.03% occurs, treatment should be symptomatic.

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In oral (by gavage) mouse and rat general toxicity studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2  is at least 70 times higher than the accidental dose of one bottle of bimatoprost ophthalmic solution 0.03% for a 10 kg child.

{ "type": "p", "children": [], "text": "In oral (by gavage) mouse and rat general toxicity studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2  is at least 70 times higher than the accidental dose of one bottle of bimatoprost ophthalmic solution 0.03% for a 10 kg child. " }

Bimatoprost ophthalmic solution 0.03% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2 [(1E,3S) 3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C25H37NO4. Its chemical structure is:

{ "type": "p", "children": [], "text": "\nBimatoprost ophthalmic solution 0.03% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2 [(1E,3S) 3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C25H37NO4. Its chemical structure is:" }

Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. Bimatoprost ophthalmic solution 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately between 270 and 320 mOsmol/kg.

{ "type": "p", "children": [], "text": "\nBimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. Bimatoprost ophthalmic solution 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately between 270 and 320 mOsmol/kg." }

Bimatoprost ophthalmic solution 0.03% contains Active: bimatoprost 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL; sodium chloride; sodium phosphate, dibasic (Heptahydrate); citric acid monohydrate; and water for injection. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.  

{ "type": "p", "children": [], "text": "Bimatoprost ophthalmic solution 0.03% contains Active: bimatoprost 0.3 mg/mL; Inactives: benzalkonium chloride 0.05 mg/mL; sodium chloride; sodium phosphate, dibasic (Heptahydrate); citric acid monohydrate; and water for injection. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.  " }

Bimatoprost, a prostaglandin analog, is a synthetic structural analog of prostaglandin with ocular hypotensive activity. It selectively mimics the effects of naturally occurring substances, prostamides. Bimatoprost is believed to lower intraocular pressure (IOP) in humans by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Elevated IOP presents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.

Absorption

After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean Cmax and AUC0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng•hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time.

Distribution

Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma.

Elimination

Metabolism

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N- deethylation and glucuronidation to form a diverse variety of metabolites.

Excretion

Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.

Carcinogenesis

Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively       (at least 192 and 291 times the human systemic exposure at the RHOD, respectively, based on blood AUC levels).

Mutagenesis

Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.

Impairment of Fertility

Bimatoprost did not impair fertility in male or female rats at doses up to 0.6 mg/kg/day (at least 103 times the human systemic exposure at the RHOD, based on blood AUC levels).

In clinical studies of patients with open angle glaucoma or ocular hypertension with a mean baseline IOP of 26 mmHg, the IOP-lowering effect of bimatoprost ophthalmic solution 0.03% once daily (in the evening) was 7-8 mmHg.

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Bimatoprost ophthalmic solution 0.03% is supplied sterile in opaque white low density polyethylene ophthalmic dispenser bottles and tips with turquoise polystyrene caps in the following sizes:

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2.5 mL fill in 5 mL container -NDC 70069-401-01

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5 mL fill in 5 mL container -NDC 70069-402-01

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7.5 mL fill in 10 mL container -NDC 70069-403-01

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Storage: Store at 2°C-25°C (36°F-77°F). After opening, bimatoprost ophthalmic solution 0.03% can be used until the expiration date stamped on the bottle.

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Potential for Pigmentation

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Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of bimatoprost ophthalmic solution 0.03%.

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Potential for Eyelash Changes

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Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with bimatoprost ophthalmic solution 0.03%. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.

{ "type": "p", "children": [], "text": "Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with bimatoprost ophthalmic solution 0.03%. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. " }

Handling the Container

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Instruct patients to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fingers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

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When to Seek Physician Advice

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Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of bimatoprost ophthalmic solution 0.03%.

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Contact Lens Use

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Advise patients that bimatoprost ophthalmic solution 0.03% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of bimatoprost ophthalmic solution 0.03% and may be reinserted 15 minutes following its administration.

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Use with Other Ophthalmic Drugs

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Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications.

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Manufactured for:

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Somerset Therapeutics, LLC

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Somerset, NJ 08873

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Customer Care # 1-800-417-9175

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Made in India

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Code No.:KR/DRUGS/KTK/28/289/97

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ST-BIM/P/04

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1201056

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2.5 mL Container Label

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2.5 mL Monocarton Label

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5 mL Container Label

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5 mL Monocarton Label

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7.5 mL Container Label

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7.5 mL Monocarton Label

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