NAME OF MEDICINE
LUMIGAN(r) (bimatoprost) 0.3 mg/mL eye drops
LUMIGAN(r) (bimatoprost) eye drops are a clear, isotonic, colourless, sterile ophthalmic solution. Bimatoprost is a white to off-white powder and is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water.
Pharmacotherapeutic group: Antiglaucoma preparations and miotics; other antiglaucoma preparations; opthalmologicals; prostaglandin analogues. ATC code: S01EE03 Bimatoprost is a novel synthetic prostamide analogue with potent ocular hypotensive activity. It selectively mimics the effects of a newly discovered naturally occurring substance, prostamide. Prostamide is biosynthesised from anandamide by a pathway involving COX-2 but not COX-1, suggesting a new pathway that leads to the synthesis of endogenous lipid amides that lower intraocular pressure (IOP). Bimatoprost and prostamides differ from prostaglandins (PGs) in that prostamides are biosynthesized from a different precursor, anandamide; bimatoprost does not stimulate any previously described prostanoid receptor; it is not mitogenic; it does not contract the human uterus; and it is electrochemically neutral. Bimatoprost reduces intraocular pressure in man by increasing aqueous humor outflow through the trabecular meshwork and enhancing uveoscleral outflow. Reduction of the intraocular pressure starts approximately 4 hours after the first administration and maximum effect is reached within approximately 8 to 12 hours. The duration of effect is maintained for at least 24 hours. Clinical studies have shown mean intraocular pressure decreases of up to 9 mmHg.
Bimatoprost penetrates the human cornea and sclera in vitro. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 ng/mL) within 1.5 hours after dosing. Mean bimatoprost Cmax values were similar on days 7 and 14 at 0.0721 and 0.0822 ng/mL respectively. The mean AUC0-24hr values were also similar on days 7 and 14 at 0.0742 and 0.096ng.hr/mL respectively, indicating that a steady systemic exposure to bimatoprost was reached during the first week of ocular dosing. The systemic exposure of bimatoprost is very low with no accumulation over time. Bimatoprost is moderately distributed into body tissues with a steady state systemic volume of distribution in humans of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 90%.
LUMIGAN(r) bimatoprost Datasheet Version 3.0 Data from in vitro studies showed that the overall extent of melanin binding was not dependent on concentration and the binding was reversible. Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing in humans. Bimatoprost then undergoes oxidation, N- deethylation and glucuronidation to form a diverse variety of metabolites. Bimatoprost is eliminated primarily by renal excretion. Up to 67% of an intravenous dose of radiolabelled bimatoprost administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes, the total blood clearance of unchanged bimatoprost was 1.5 L/hr/kg. After twice daily dosing, the mean AUC0-24hr value of 0.0634 ng.hr/mL for bimatoprost in the elderly (subjects 65 years or older) was statistically significantly higher than that of 0.0218 ng.hr/mL in young healthy adults, suggesting the existence of an age effect. However, this finding is not clinically relevant as systemic exposure for elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.
LUMIGAN(r) is indicated as monotherapy for the reduction of elevated intraocular pressure (IOP) in patients with chronic glaucoma or ocular hypertension; or as adjunctive therapy in patients not adequately controlled on other agents.
Elevated IOP presents a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of optic nerve damage and glaucomatous visual field loss. Bimatoprost has the action of lowering intraocular pressure with no clinically relevant effects on heart rate and blood pressure observed in clinical trials.
The efficacy of bimatoprost eye drops was demonstrated in two multi-centre studies comparative with timolol 0.5% after 6 months treatment in subjects with chronic glaucoma or ocular hypertension. In each, both once daily and twice daily bimatoprost was compared to twice daily timolol 0.5%. A total of 1198 patients were enrolled in the two studies with 474 receiving bimatoprost once daily, 483 receiving bimatoprost twice daily and 241 receiving timolol. Pooled efficacy data from the two clinical studies demonstrates that in the intent-to-treat population bimatoprost 0.03% ophthalmic solution, administered both once and twice daily as a monotherapy agent is superior to timolol 0.5% twice daily over a six month period at hours 0, 2 and 8 (p 0.05). At the primary endpoint (hour 0 at month 6) mean decrease from baseline IOP in patients treated with bimatoprost once daily was -8.28 mmHg and was superior to that in patients treated with timolol (-6.44 mmHg, p < 0.001). At the primary endpoint (hour 0 at month 6) the mean decrease from baseline IOP in patients treated with bimatoprost once daily was -8.28 mmHg and was superior to that in patients treated with bimatoprost twice daily (-7.15 mmHg, p < 0.001). Therefore, twice daily dosing did not show any increased efficacy compared to once daily dosing. Mean IOP changes from baseline for bimatoprost once daily range from 7.01 mmHg to 8.75 mmHg from hours 0 to 8 over the six month period of evaluation. The similar range for timolol was 4.38 mmHg to 6.44 mmHg.
LUMIGAN(r) bimatoprost Datasheet Version 3.0 Overall, bimatoprost once daily produced a reduction in IOP of 33%. Timolol twice daily produced a reduction of 23%. In addition to mean change from baseline, a frequency analysis of the IOP recorded at hour 0 at each visit was performed. Consistently 50% of patients achieved an IOP of 17 mmHg or less (a commonly agreed 'target IOP') with bimatoprost once daily over the time period studied, compared to approximately 30% in the timolol group. In addition, those whose IOP was recorded as over 22 mmHg were consistently less than 10% in the bimatoprost group compared to approximately 20% in the timolol group. These results provide positive clinical interpretation to the statistical superiority of the once daily regimen over timolol seen at all visits at hours 0, 2 and 8.
The ability of LUMIGAN(r) 0.03% eye drops to lower IOP when used as adjunctive therapy to topical beta-blocker monotherapy has been evaluated in two large scale multi-centre, randomised 3 month studies, involving 722 patients of which 489 received bimatoprost. The numbers and proportions of the different topical beta-blocking agents used in the studies were representative of clinical practice. For the bimatoprost once daily/ beta-blocker regimen hour 0, mean decreases from baseline were consistent over the three month period studied. The values ranged from 6.97 to 7.74 mmHg. In the first study, bimatoprost 0.03% once or twice daily as an adjunct to beta-blocker therapy was compared with latanoprost 0.005% ophthalmic solution once daily, as an adjunct to beta- blocker therapy. At month 3, the mean decreases in IOP from baseline at hours 0, 2 and 8 in patients treated with bimatoprost once daily/beta-blocker in the intent to treat population ranged from 6.03 to 7.95 mmHg. These were non-inferior to the decreases seen in the latanoprost/ beta-blocker group (5.89 to 7.35 mmHg) at all time points. At the primary endpoint (hour 0 at month 3) mean decrease from baseline IOP in patients treated with bimatoprost once daily/beta-blocker was -7.95 mmHg and was non-inferior to that in patients treated with latanoprost/beta-blocker (-7.35 mmHg). At the primary endpoint (hour 0 at month 3) mean decrease from baseline IOP in patients treated with bimatoprost twice daily/beta- blocker was -7.26 mmHg and was non-inferior to that in patients treated with latanoprost/beta-blocker (-7.35 mmHg). Mean changes from baseline hour 0 IOP across all follow-up visits ranged from -7.23 to -7.95 mmHg with bimatoprost once daily/beta-blocker, and from -6.91 to -7.53 mmHg with latanoprost/beta-blocker. The decrease in IOP from baseline hour 0 was statistically significant within each treatment group at each follow-up visit (p < 0.001). In the second study, bimatoprost 0.03% once or twice daily as an adjunct to beta-blocker therapy was compared with vehicle twice daily, as an adjunct to beta-blocker therapy. At month 3, the mean decreases in IOP from baseline at hours, 0, 2 and 8 in patients treated with bimatoprost once daily/beta-blocker in the intent to treat population ranged from 6.39 to 7.38 mmHg. These were superior to the decreases seen in the vehicle/beta-blocker group (2.62 to 3.59 mmHg) at all time points (p< 0.001). At the primary endpoint (hour 0 at month 3) mean decrease from baseline IOP in patients treated with bimatoprost once daily/beta-blocker was -7.38 mmHg and was superior to that in patients treated with vehicle/beta-blocker (-3.59 mmHg, p < 0.001). At the primary endpoint (hour 0 at month 3) mean decrease from baseline IOP in patients treated with bimatoprost twice daily/beta-blocker was -6.34 mmHg and was superior to that in patients treated with vehicle/beta-blocker (-3.59 mmHg, p < 0.001). Mean decreases from baseline hour 0 IOP across all follow-up visits ranged from 6.53 to 7.38 mmHg with bimatoprost once daily/beta-blocker, and from 2.04 to 3.59 mmHg with vehicle/beta-blocker. Mean decreases from baseline IOP at hours 0, 2 and 8 were superior to those seen in the vehicle/beta-blocker group at each time point at each follow-up visit (p < 0.001 in the bimatoprost once daily/beta-blocker group; p 0.003 in the bimatoprost twice daily/beta-blocker group). In a pooled analysis of both studies, at the primary endpoint (hour 0 at month 3) the mean decrease from baseline IOP in patients treated with bimatoprost once daily/beta-blocker was
LUMIGAN(r) bimatoprost Datasheet Version 3.0 -7.74 mmHg and was superior to that in patients treated with bimatoprost twice daily/beta- blocker (-6.89 mmHg, p = 0.017).
Monotherapy: The recommended dose is one drop of LUMIGAN(r) in the affected eye(s) once daily, administered in the evening. Adjunctive Therapy: The recommended dose is one drop of LUMIGAN(r) in the affected eye(s) once daily, administered in the evening. More frequent administration has not been shown to provide increased efficacy. If more than one topical ophthalmic medication is to be used, the other medication should not be used within 5 minutes of using LUMIGAN(r) eye drops. In order to minimise systemic absorption of LUMIGAN(r) eye drops, patients should be instructed to apply pressure to the tear duct immediately following administration of the drug.
Safety and effectiveness in patients below 18 years of age have not been established.
No dosage adjustment in elderly patients is necessary.
LUMIGAN(r) eye drops are contraindicated in patients with hypersensitivity to bimatoprost or to any component of the medication.
LUMIGAN(r) has not been studied in patients with heart block more severe than first degree or uncontrolled congestive heart failure. There have been a limited number of spontaneous reports of bradycardia or hypotension with LUMIGAN(r) eye drops. LUMIGAN(r) should be used with caution in patients predisposed to low heart rate or low blood pressure. LUMIGAN(r) has not been studied in patients with compromised respiratory function and should therefore be used with caution in such patients. In clinical studies, in those patients with a history of a compromised respiratory function, no significant untoward respiratory effects have been seen. LUMIGAN(r) has not been studied in patients with renal or hepatic impairment and should therefore be used with caution in such patients. During treatment with LUMIGAN(r), darkening of the eyelid skin and gradual increased eyelash growth (lengthening, darkening and thickening) with no consequent untoward ocular effects
LUMIGAN(r) bimatoprost Datasheet Version 3.0 have been observed. Increased iris pigmentation has also been reported. The change in iris pigmentation occurs slowly and may not be noticeable for several months to years. The effect has been seen in up to 2% of patients treated with LUMIGAN(r) for up to 6 months. At 12 months, the incidence of iris pigmentation with LUMIGAN was 1.5% and did not increase following 3 years of treatment. The long-term effects of increased iris pigmentation are not known. Before treatment is initiated,patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent and may lead to differences in appearance between the eyes when only one eye is treated. There is the potential for hair growth to occur in areas where LUMIGAN solution comes repeatedly in contact with the skin surface. Thus, it is important to apply LUMIGAN as instructed and to avoid it running onto the cheek or other skin areas. In LUMIGAN(r) studies in patients with glaucoma or ocular hypertension, it has been shown that more frequent exposure of the eye to more than one dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using LUMIGAN(r) with other prostanglandin analogues should be monitored for changes to their intraocular pressure.
LUMIGAN
should be used with caution in patients with active intraocular inflammations (e.g. uveitis) because the inflammation may be exacerbated.
Macular oedema, including cystoid macular oedema, has been reported during treatment with bimatoprost 0.03% ophthalmic solution for elevated IOP. LUMIGAN(r) 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 oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy). LUMIGAN(r) has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.
Ocular administration of bimatoprost in monkeys at concentrations of 0.03% or 0.1% once or twice daily for 1 year caused an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. No associated increase in melanocyte number was observed with the pigmentation. It appears that the mechanism of increased iris pigmentation is due to increased stimulation of melanin production in melanocytes and not to an increase in melanocyte number. Periocular effects were also observed in an intravenous toxicity study at systemic exposures at least 235-fold higher than that observed in humans after ocular administration. No functional or microscopic changes related to the periocular effects were observed. The mechanism of action for the observed periocular changes is unknown.
The carcinogenic potential of orally administered (gavage) bimatoprost was evaluated in mice given 0.3, 1.0 or 2.0 mg/kg/day and in rats given 0.1, 0.3 or 1.0 mg/kg/day for 104 weeks. There was no evidence of tumorigenic potential at any of the administered dosages in either species. In the rat carcinogenicity study, a dose-related increase in vacuolated corpora lutea was observed. The ovarian effects in rats is believed to be species specific. Bimatoprost was not mutagenic or clastogenic in a bacterial mutation assay, in a mouse lymphoma test in vitro or in a mouse micronucleus test.
LUMIGAN(r) bimatoprost Datasheet Version 3.0 Bimatoprost did not affect fertility in male or female rats at oral doses up to 0.6 mg/kg/day (approximately 103 times the intended human exposure).
Pregnancy Category B3
In embryo/ foetal development studies in pregnant mice and rats abortion but no developmental effects were observed at doses that were at least 33 or 97 times higher, respectively, than the intended human exposure. In peri/postnatal studies in rats, reduced gestation time, foetal death and decreased pup body weights were observed in dams given 0.3 mg/kg/day (a rodent-specific pharmacological effect; systemic exposure estimated to be at least 41 times the intended human exposure). This maternal toxicity likely resulted in decreased mating performance and gestational body weight gain in the offspring, but neurobehavioural functions were not affected. There are no adequate and well-controlled studies in pregnant women. LUMIGAN(r) should not be used during pregnancy unless clearly necessary.
Bimatoprost was excreted in rat milk following PO administration. Increased pup mortality and depressed pup growth occurred when dams were treated PO with bimatoprost from gestation day 7 to lactation day 20 at 0.3 mg/kg/day, corresponding to exposures approximately 41 times the expected human exposure. There are no data on the excretion of bimatoprost into human milk or on the safety of bimatoprost exposure in infants. Because many drugs are excreted in human milk, nursing women who use LUMIGAN(r) should stop breast feeding.
Based on the pharmacodynamic profile, bimatoprost is not expected to affect the ability to drive and use machines. As with any ocular medication, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.
LUMIGAN(r) eye drops contain the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN(r) and may be reinserted 15 minutes following administration. LUMIGAN(r) should not be administered while wearing contact lenses. The tip of the bottle should not be allowed to contact the eye, surrounding structures, fingers or any other surface in order to avoid contamination of the solution.
In the two pivotal monotherapy trials (715 patients), the most frequently reported treatment- related adverse events were: conjunctival hyperaemia in up to 42%, growth of eyelashes in up to 36% and ocular pruritus in up to 14% of patients. The incidence of conjunctival hyperaemia at baseline was 25.1% and 17.8% in patients allocated to treatment with LUMIGAN(r) once daily and timolol twice daily, respectively. At 6 months, the incidence of patients with a greater than mild increase in conjunctival hyperaemia was 6.2% and 0.4% in
LUMIGAN(r) bimatoprost Datasheet Version 3.0 patients treated with LUMIGAN(r) once daily and timolol twice daily, respectively. Less than 7% of patients discontinued due to any adverse event. The following undesirable effects definitely, probably or possibly related to treatment were
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reported during clinical trials with LUMIGAN . Most were ocular, mild to moderate, and none was serious:
Eye Disorders:
Very common:conjunctival hyperaemia, growth of eyelashes, ocular pruritus. Common:allergic conjunctivitis, asthenopia, blepharitis, blepheral pigmentation, conjunctival oedema, corneal erosion, eye discharge, eyelash darkening, eyelid erythema, eyelid pruritus, eye pain, foreign body sensation, increased iris pigmentation, lacrimation increased, ocular burning, ocular dryness, ocular irritation, photophobia, pigmentation of periocular skin, superficial punctate keratitis, tearing, visual disturbance/blurred vision and worsening of visual acuity. Uncommon:blepharospasm, eyelid oedema, eyelid retraction, iritis, retinal haemorrhage.
Nervous system disorders:
Common:headache Uncommon:depression, vertigo
Musculoskeletal and connective tissue disorders:
Common:asthenia
Respiratory, thoracic and mediastinal disorders:
Uncommon:infection (primarily colds and upper respiratory tract infections)
Skin and subcutaneous tissue disorders:
Common:Skin hyperpigmentation Uncommon:Hirsutism
Post-marketing Experiences: Eye disorders:
Deepened lid sulcus (enophthalmos), erythema (periorbital), macular oedema
Skin and subcutaneous tissue disorders:
Hair growth abnormal Gastrointestinal disorders: Nausea
LUMIGAN(r) bimatoprost Datasheet Version 3.0
Nervous system disorders:
Dizziness
Vascular disorders:
Hypertension
No interaction studies have been performed. No drug-drug interactions are anticipated in humans since systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/mL) following ocular dosing. No effects on hepatic drug metabolising enzymes were observed in pre-clinical studies. Therefore, specific interaction studies with other medicinal products have not been performed with LUMIGAN(r). In clinical studies, LUMIGAN(r) was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of drug interactions. Concomitant use of LUMIGAN(r) and antiglaucoma agents other than topical beta-blockers has not been evaluated during adjunctive glaucoma therapy. There is a potential for the IOP-lowering effect of prostaglandin analogues to be reduced in patients with glaucoma or ocular hypertension when used with other prostaglandin analogues.
If overdosage occurs, treatment should be symptomatic and supportive. Ophthalmic overdose: No case of overdose has been reported, and is unlikely to occur after ocular administration. Systemic overdose resulting from accidental ingestion: If LUMIGAN(r) is accidentally ingested, the following information may be useful: in two-week oral rat and mouse studies, doses up to 250 mg/kg/day did not produce any toxicity. This dose expressed as mg/kg is 1,100 times higher than the accidental dose of one bottle (7.5mL) of LUMIGAN(r) in a 10 kg child.
To avoid contamination of the solution, keep container tightly closed. Do not touch dropper tip to any surface. Contents are sterile if seal is intact. Shelf life: 2 years Storage: Store below 25degC Discard contents 4 weeks after opening the bottle.
Prescription Medicine
LUMIGAN(r) bimatoprost Datasheet Version 3.0
LUMIGAN(r) (bimatoprost) 0.3mg/mL eye drops are supplied in plastic dropper bottles with a plastic screw cap. Each bottle has a fill volume of 3mL.
PRESERVATIVE: benzalkonium chloride INACTIVES: sodium phosphate dibasic; citric acid monohydrate; sodium chloride; and water - purified. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.
Allergan New Zealand Ltd, Cnr Manu Tapu Drive & Joseph Hammond Place, Auckland International Airport, Mangere Auckland, NEW ZEALAND Toll free telephone: 0800 659 912
4 May 2012
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Registered Trademark of Allergan Inc.
LUMIGAN(r) bimatoprost Datasheet Version 3.0