LUMIGAN 0.01% (bimatoprost ophthalmic solution) 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.
Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. LUMIGAN 0.01% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.
LUMIGAN 0.01% contains bimatoprost 0.3 mg/bottle of 3 mL (0.1 mg/mL).
Excipients/Inactive Ingredients: Sodium chloride, dibasic sodium phosphate, citric acid and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.
Preservative: Benzalkonium chloride 0.6 mg/bottle of 3 mL (0.2 mg/mL).
Pharmacotherapeutic group: Other antiglaucoma preparations. ATC code: S01EE03.
Pharmacology: Mechanism of Action: Bimatoprost is a synthetic prostamide structurally related to prostaglandin F2α (PGF2α).
Bimatoprost is a potent ocular hypotensive agent.
Bimatoprost efficacy may be related to a dual mechanism of action on aqueous humour outflow that involves uveoscleral and trabecular meshwork Schlemm's canal pathways. Studies in human models of the trabecular meshwork/Schlemm's canal outflow pathways have demonstrated that bimatoprost produces marked increases in hydraulic conductivity that are prostamide receptor mediated.
Pharmacokinetics: Absorption and Systemic Drug Exposure: Bimatoprost penetrates the human cornea and sclera well in vitro. The mean corneal permeability coefficient was 3.24 x 10-6 cm/sec. Bimatoprost penetrated human scleral tissue better than corneal tissue with a mean scleral permeability coefficient of 14.5 x 10-6 cm/sec. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of 1 drop of 0.03% bimatoprost to both eyes of healthy subjects for 2 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 Cmax and AUC0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng·hr/mL respectively, indicating that a steady drug concentration was reached during the first week of ocular dosing.
The blood concentrations of bimatoprost from patients with glaucoma or ocular hypertension in 2 Phase 3 safety and efficacy studies were measured (N=88 on once-daily treatment and N=89 on twice-daily treatment). The samples were collected at approximately 5 minutes after the evening dose on day 0 and at 3, 6 and 12 months. Bimatoprost blood concentrations were similar to those observed in normal, healthy subjects and there was no significant systemic drug accumulation over time. The C-1 acid metabolite (AGN 191522) was typically not measurable in blood samples from these studies.
Distribution: Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in human at steady-state was 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Bimatoprost was approximately 88% bound to human plasma proteins at concentrations ranging from 1 to 250 ng/mL that was concentration independent. Up to 20% of bimatoprost was bound reversibly to synthetic melanin at concentrations ranging from 0.2-100 μg/mL which was also concentration independent.
Metabolism: Bimatoprost is not extensively metabolized in human eye and it is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes glucuronidation, hydroxylation, N-deethylation and deamidation to form a diverse variety of metabolites. The glucuronide conjugates of bimatoprost are the most abundant metabolite excreted in urine and faeces. There is evidence that hydrolysis of bimatoprost to the free acid is not a prerequisite for its ocular hypotensive activity.
The effects of bimatoprost treatment on hepatic drug metabolizing enzymes was investigated in rats and monkeys following one month of daily intravenous administration. Systemic drug exposures were at least 4,000 times greater than those seen in humans following QD ophthalmic administration. Bimatoprost was found to have no significant effect on any of the hepatic microsomal enzyme activities in cynomolgus monkeys. In female rats, an increase in the activity of UDP-glucuronosyl transferase was observed. In the male rats, a marginal reduction in the rate of testosterone 16β-hydroxylation were the only findings. Neither of these observations is expected to have any clinically significant consequences in humans.
Elimination: Following an intravenous dose of radiolabeled bimatoprost (3.12 μg/kg) to six healthy subjects, the mean maximum blood concentration of total radioactivity was 14.5 ng·eq/mL. Total radioactivity was eliminated from the body with a short half-life of 1.74 hours. The blood concentration of intact bimatoprost was 12.2 ng/mL at maximum and declined rapidly with an elimination half-life of 0.771 hour (approximately 45 minutes). Blood concentrations of AGN 191522, the C-1 acid metabolite, were much lower than those of bimatoprost as peak concentration was 0.12 ng/mL. The total blood clearance (Clb) of unchanged bimatoprost was 1.50 L/hr/kg.
Sixty-seven percent of the administered dose of bimatoprost was excreted in the urine with only a small fraction excreted as unchanged drug. Twenty-five percent of the dose was recovered in feces of which 15-40% was eliminated as unchanged drug.
Pharmacokinetic in Special Clinical Situations: Characteristic in Elderly Patients: There was no significant systemic accumulation of bimatoprost following twice-daily dosing for 7 days in either young (18-44 years, mean=28.5) or elderly patients (65-80 years, mean=71.0). Bimatoprost appeared rapidly in the blood in both age groups, and was below the LLOQ by 1.5 hours in most patients. Systemic exposure was higher in the elderly than the young following both single and multiple dosing (124% and 213%, respectively). The mean AUC0-24hrs value of 0.0634 ng·hr/mL in elderly subjects was statistically significantly higher than that of 0.0218 ng·hr/mL in young subjects, suggesting the existence of an age effect. However, this finding is not considered clinically relevant as bimatoprost exhibits similar efficacy and safety profiles in both the young and elderly populations.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks.
Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.
No impairment of fertility occurred in rats when males were treated for 70 days prior to cohabitation and females were treated for 15 days prior to mating. Treatment was continued in males until copulation was observed and in females through gestation day 7.
The highest doses (0.6 mg/kg/day) achieved systemic exposure that was 103 times that observed in humans treated with 1 drop of 0.03% bimatoprost in each eye once daily for 2 weeks.
Clinical Studies: In a 3 month clinical study of patients with open angle glaucoma or ocular hypertension with an average baseline IOP of 23.5 mmHg, the IOP-lowering effect of LUMIGAN 0.01% once daily (in the evening) was up to 7.5 mmHg. In this same study, LUMIGAN 0.01% also had a similar overall safety profile compared with LUMIGAN 0.03%. After 12 months of treatment, discontinuations were 8.1% for LUMIGAN 0.01%.
LUMIGAN 0.01% (bimatoprost ophthalmic solution) is a prostaglandin analog 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. LUMIGAN 0.01% (bimatoprost ophthalmic solution) should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen 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.
LUMIGAN 0.01% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, each one should be administered at least five (5) minutes apart.
No information is available on overdosage in humans. If overdose with LUMIGAN 0.01% (bimatoprost ophthalmic solution) occurs, treatment should be symptomatic and supportive.
If LUMIGAN 0.01% is accidentally ingested, the following information may be useful: in 2-week oral mouse and rat studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 160 times higher than the accidental dose of one bottle of LUMIGAN 0.01% for a 10 kg child.
LUMIGAN 0.01% is contraindicated in patients with clinically significant hypersensitivity to bimatoprost or to any of the excipients.
Pigmentation: Bimatoprost ophthalmic solution has been reported to cause changes to pigmented tissues. When LUMIGAN 0.03% (multidose) was instilled directly into the eye (for treatment of elevated IOP), the most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Periorbital tissue pigmentation has been reported to be reversible in some patients. Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes seen with ophthalmic administration of bimatoprost 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 LUMIGAN 0.01% (bimatoprost ophthalmic solution) can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. (See Potential for Pigmentation under Patient Counselling Information.)
Eyelash Changes/Potential hair growth: LUMIGAN 0.01% 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.
There is the potential for hair growth to occur in areas where LUMIGAN 0.01% solution comes repeatedly in contact with the skin surface. Thus, it is important to apply LUMIGAN 0.01% as instructed and to avoid it running onto the cheek or other skin areas.
Before treatment is initiated, patients should be informed of the possibility of eyelash growth since this has been observed during treatment with prostaglandin analogues, including LUMIGAN.
Intraocular Inflammation: LUMIGAN 0.01% should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.
Macular Edema: Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution for elevated IOP.
LUMIGAN 0.01% should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors edema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).
Angle-closure, Inflammatory or Neovascular Glaucoma: LUMIGAN 0.01% has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.
Bacterial Keratitis: 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 ocular disease. Patients with a disruption of the ocular epithelial surface are at greater risk of developing bacterial keratitis.
Patient should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid eye injury and contamination of the solution. (See Handling the Container under Patient Counselling Information.)
Use with Contact Lenses: LUMIGAN 0.01% contains the preservative benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact lenses. Patients wearing soft (hydrophilic) contact lenses should be instructed to remove contact lenses prior to administration of LUMIGAN 0.01% and wait at least 15 minutes following administration before reinserting soft contact lenses.
Use with Prostaglandin Analogs: In LUMIGAN 0.03% 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 with other prostaglandin analogs should be monitored for changes to their intraocular pressure.
Hepatic Impairment: LUMIGAN 0.01% has not been studies in patients with moderate to severe hepatic impairment and should therefore be used with caution in such patients. In patients with a history of mild liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver function over 48 months.
LUMIGAN 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 were seen.
Renal Impairment: There are no data specific for this patient population and the product should therefore be used with caution in such patients.
Effects on Ability to Drive and Operate Machine: As with any ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.
Use in Children: Use in pediatric patients has not been evaluated and therefore use is not recommended in children or adolescents.
Use in the Elderly: No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.
Pregnancy: Pregnancy Category C.
Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels.
At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced.
There are no adequate and well-controlled studies of LUMIGAN 0.01% (bimatoprost ophthalmic solution) administration in pregnant women. Because animal reproductive studies are not always predictive of human response LUMIGAN 0.01% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: It is not known whether LUMIGAN 0.01% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when LUMIGAN 0.01% is administered to a nursing woman.
Clinical Studies Experience: In a 12-month, Phase 3 clinical study, in patients with glaucoma or ocular hypertension (Study Report 192024-031), approximately 38% (71/185) of patients treated with bimatoprost 0.01% eye drops solution experienced undesirable effects considered related to treatment. The most frequently reported treatment-related adverse event was conjunctival hyperemia (mostly mild and thought to be of a non-inflammatory nature) occurring in 29% of patients. Approximately 4% (8/185) of patients in the bimatoprost 0.01% arm of the study discontinued due to any adverse event in the 12-month study, with 1.6% (3/185) discontinuing due to conjunctival hyperemia.
The following undesirable effects considered related to treatment were reported during treatment with bimatoprost 0.01% eye drops (Study Report 192024-031, 12-months). Most were ocular, mild and none was serious.
The frequency is defined as follows: Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000).
Eye disorders: Very Common: Ocular/Conjunctival hyperemia.
Common: Eye irritation, erythema of eyelid, eye pruritus, eyelids pruritus, growth of eyelashes, punctate keratitis.
Skin and subcutaneous tissue disorders: Common: Hypertrichosis, skin hyperpigmentation.
General disorders and administration site conditions: Common: Instillation site irritation.
Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of LUMIGAN 0.01% in clinical practice. Because they are reported voluntarily from a population of unknown size, it is not possible to reliably estimate the frequency of these reactions:
Eye disorders: Blepharal pigmentation, dry eye, eye discharge, eye edema, eyelid edema, eye pain, foreign body sensation in eye, iris hyperpigmentation, lacrimation increased, macular edema, ocular discomfort, periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus, eyelid ptosis, enophthalmos and eyelid retraction, photophobia, vision blurred.
Immune system disorders: Hypersensitivity reaction including sign and symptoms of eye allergy and allergic dermatitis.
Nervous system disorders: Dizziness, headache.
Respiratory, thoracic and mediastinal disorders: Asthma, exacerbation of asthma, dyspnea.
Vascular disorders: Hypertension.
Inform the doctor of undesirable effects occurred during drug use.
No interaction studies have been performed.
No interactions are anticipated in humans, since systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/mL) following ocular dosing with bimatoprost 0.03% eyedrops. Bimatoprost is biotransformed by any of multiple enzymes and pathways, and no effects on hepatic drug metabolizing enzymes were observed in preclinical studies in rats and monkeys.
In clinical studies, LUMIGAN 0.03% eye drops (multidose) was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of interactions.
Concomitant use of LUMIGAN and antiglaucomatous 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 analogs (e.g., LUMIGAN) to be reduced in patients with glaucoma or ocular hypertension when used with other prostaglandin analogs.
LUMIGAN 0.01% should be stored below 30°C. Discard unused contents 4 weeks after opening.
Shelf-life: 24 months from manufacturing date.
S01EE03 - bimatoprost ; Belongs to the class of prostaglandin analogues. Used in the treatment of glaucoma and hypotrichosis of the eyelashes.
Lumigan 0.01% ophth soln 0.01%
3 mL x 1's
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