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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 09.04.2022
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Locular is indicated for the symptomatic treatment of facial erythema of rosacea in adult patients.
Locular® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15% is an alpha adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
Posology
One application per 24 hours, at any time suitable for the patient, for as long as facial erythema is present.
The maximum daily recommended dose is 1 g of gel in total weight, which corresponds to approximately five pea sized amounts.
Treatment should be initiated with a smaller amount of gel (less than the maximum) for at least one week. The amount of gel can then be increased gradually based on tolerability and patient response.
Special populations
Elderly patients
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Paediatric population
The safety and efficacy of Locular in children and adolescents aged less than 18 years have not been established. No data are available.
Locular is contraindicated in children aged less than 2 years because of serious systemic safety risk. Safety concerns related to the systemic absorption of brimonidine have also been identified for the age group 2 to 12 years. Locular should not be used in children or adolescents aged 2 to 18 years.
Method of administration
Cutaneous use only.
Locular should be applied smoothly and evenly as a thin layer across the entire face (forehead, chin, nose and both cheeks) avoiding the eyes, eyelids, lips, mouth and membrane of the inner nose. Locular should be applied only to the face.
Hands should be washed immediately after applying the medicinal product.
Locular can be used in conjunction with other cutaneous medicinal products for the treatment of inflammatory lesions of rosacea and with cosmetics. These products should not be applied immediately before the daily application of Locular; they may be used only after the applied Locular has dried.
The recommended dose is one drop of Locular® P (brimonidine tartrate) in the affected eye(s) three times daily, approximately 8 hours apart. Locular® P (brimonidine tartrate) ophthalmic solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Children aged less than 2 years.
Patients receiving monoamine oxidase (MAO) inhibitor therapy (for example selegiline or moclobemide) and patients on tricyclic (such as imipramine) or tetracyclic (such as maprotiline, mianserin or mirtazapin) antidepressants which affect noradrenergic transmission.
Neonates and Infants (under the age of 2 years)
Locular® P (brimonidine tartrate) is contraindicated in neonates and infants (under the age of 2 years).
Hypersensitivity Reactions
Locular® P (brimonidine tartrate) is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.
Locular should not be applied on irritated skin (including following laser therapy) or open wounds. In case of severe irritation or contact allergy, the treatment with the medicinal product should be discontinued.
Exacerbation of rosacea symptoms is very common in patients treated with Locular. Across all clinical studies, 16% of patients receiving Locular experienced an event of symptom exacerbation. Treatment should be initiated with a small amount of gel and the dose increased gradually, based on tolerability and response to treatment.
Erythema and Flushing
The effect of Locular topical gel begins to diminish hours after application. In some patients, erythema and flushing were reported to return with greater severity than was present at baseline. Most of the cases were observed within the first 2 weeks of starting the treatment.
The onset of flushing relative to application of Locular topical gel varied, ranging from approximately 30 minutes to several hours.
In the majority of these cases, erythema and flushing resolved after discontinuation of Locular topical gel.
In case worsening of erythema occurs, Locular topical gel should be discontinued. Symptomatic measures, such as cooling, NSAID and antihistamines, may help in alleviating symptoms.
Recurrences of aggravated erythema and flushing have been reported after re-administration of Locular topical gel. Prior to resuming treatment after temporary discontinuation due to aggravated erythema or flushing, perform a test application on a small area of the face for at least one day before full facial application is resumed.
It is important to inform the patient not to exceed the recommended maximum dose (5 pea size amounts) and frequency of application (once daily).
Locular should not be applied close to the eyes.
Locular has not been studied in patients with renal or hepatic impairment.
Any increase in the daily amount applied above 5 pea sized amounts and/or increase in frequency of daily application of the medicinal product should be avoided, since the safety of higher daily doses or repeated daily application has not been assessed.
The concomitant use of other systemic alpha adrenergic receptor agonists may potentiate the undesirable effects of this class of medicinal products in patients:
- with severe or unstable or uncontrolled cardiovascular disease;
- with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, thrombangiitis obliterans, scleroderma, or Sjögren's syndrome.
The medicinal product contains methylparahydroxybenzoate (E218) which may cause allergic reactions (possibly delayed), and propylene glycol which may cause skin irritation.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Potentiation of Vascular Insufficiency Locular® P (brimonidine tartrate) may potentiate syndromes associated with vascular insufficiency. Locular® P (brimonidine tartrate) should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
Severe Cardiovascular Disease
Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.
Contamination of Topical Ophthalmic Products After Use
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 (see PATIENT INFORMATION).
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No compound-related carcinogenic effects were observed in either mice or rats following a 21month and 24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats achieved 150 and 120 times or 90 and 80 times, respectively, the plasma Cmax drug concentration in humans treated with one drop of Locular® P (brimonidine tartrate) 0.1% or 0.15% into both eyes 3 times per day, the recommended daily human dose.
Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.
Reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses which achieve up to approximately 125 and 90 times the systemic exposure following the maximum recommended human ophthalmic dose of Locular® P (brimonidine tartrate) 0.1% or 0.15%, respectively.
Use In Specific Populations
Pregnancy
Pregnancy Category B: Teratogenicity studies have been performed in animals.
Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5.0 mg/kg/day) achieved AUC exposure values 360- and 20-fold higher, or 260- and 15-fold higher, respectively, than similar values estimated in humans treated with Locular® P (brimonidine tartrate) 0.1% or 0.15%, 1 drop in both eyes three times daily.
There are no adequate and well-controlled studies in pregnant women; however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction studies are not always predictive of human response, Locular® P (brimonidine tartrate) should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from Locular® P (brimonidine tartrate) in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Locular® P (brimonidine tartrate) is contraindicated in children under the age of 2 years (see CONTRAINDICATIONS). During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. The safety and effectiveness of brimonidine tartrate have not been studied in children below the age of 2 years.
In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50-83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age ( > 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
Special Populations
Locular® P (brimonidine tartrate) has not been studied in patients with hepatic impairment.
Locular® P (brimonidine tartrate) has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known.
Locular has no or negligible influence on the ability to drive and use machines.
Summary of the safety profile
The most commonly reported adverse reactions are erythema, pruritus, flushing and skin burning sensation, all occurring in 1.2 to 3.3% of patients in clinical studies. They are typically mild to moderate in severity, and usually do not require discontinuation of treatment. No meaningful differences in the safety profiles were observed between the elderly subject population and subjects 18 to 65 years of age. Aggravated erythema, flushing and skin burning sensation have been reported during the post-marketing period.
Tabulated list of adverse reactions
The adverse reactions are classified by System Organ Class and frequency, using the following convention: 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), not known (cannot be estimated from the available data) and were reported with Locular in clinical studies (see Table 1).
Table 1 - Adverse reactions
| System Organ Class | Frequency | Adverse reactions |
| Cardiac disorders | Rare | Bradycardia* |
| Nervous system disorders | Uncommon | Headache, paraesthesia |
| Eye disorders | Uncommon | Eyelid oedema |
| Vascular disorders | Common | Flushing, pallor at the application site* |
| Uncommon | Dizziness* | |
| Rare | Hypotension* | |
| Respiratory, thoracic and mediastinal disorders | Uncommon | Nasal congestion |
| Gastrointestinal disorders | Uncommon | Dry mouth |
| Skin and subcutaneous tissue disorders | Common | Erythema, pruritus, skin burning sensation |
| Uncommon | Acne, allergic contact dermatitis, contact dermatitis, dermatitis, dry skin, pain of skin, skin discomfort, rash papular, rosacea, skin irritation, skin warm, swelling face*, urticaria* | |
| Rare | Angioedema* | |
| General disorders and administration site conditions | Uncommon | Feeling hot, peripheral coldness |
* Adverse reactions reported from post-marketing data.
Description of selected adverse reactions
Bradycardia and hypotension
Post-marketing cases of bradycardia, hypotension (including orthostatic hypotension) and dizziness have been reported, some of which required hospitalization. Some cases involved application of Locular following laser procedures.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Adverse reactions occurring in approximately 10-20%of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5-9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance.
Adverse reactions occurring in approximately 1-4% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: abnormal taste, allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), insomnia, keratitis, lid disorder, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity.
The following reactions were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness, and taste perversion.
Postmarketing Experience
The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.
Overdoses after oral use of other alpha2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.
Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.
No cases of overdose after cutaneous use of Locular were reported during the clinical development program.
Paediatric population
Serious adverse reactions following inadvertent ingestion of Locular by two young children of one clinical study subject have been reported. The children experienced symptoms consistent with previously reported oral overdoses of alpha2-agonist in young children. Both children were reported to have made a full recovery within 24 hours.
Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse reaction reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving Locular® P (brimonidine tartrate) as part of medical treatment of congenital glaucoma or by accidental oral ingestion (see Use In Specific Populations). Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.
Pharmacotherapeutic group: Other dermatological preparations, Other dermatologicals,
ATC code: D11AX21.
Mechanism of action
Brimonidine is a highly selective alpha2-adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha1-adrenergic receptor.
Pharmacodynamic effects
Cutaneous facial application of a highly selective alpha2-adrenergic receptor agonist reduces erythema through direct cutaneous vasoconstriction.
Clinical efficacy and safety
The efficacy of Locular in the treatment of moderate to severe facial erythema of rosacea has been demonstrated in two randomised, vehicle controlled blinded clinical trials, which were identical in design. Moderate to severe erythema was defined as a grade 3 or greater on both the Clinician Erythema Assessment (CEA) scale and Patient Self-Assessment (PSA) scale. The studies were conducted in 553 randomised subjects aged 18 years and older who were treated once daily for 4 weeks with either Locular or vehicle. Of these, 539 completed 29 days of treatment and had data available to be included in the efficacy analysis at Day 29, with the majority being Caucasians between 18 and 65 years of age.
The primary endpoint was expressed in terms of composite success i.e. subjects responding with a 2-grade reduction on both baseline CEA score and baseline PSA score on Day 29. The results from both clinical studies demonstrated that Locular was significantly more effective (p<0.001) in the reduction of facial erythema of rosacea than vehicle gel when applied once daily for 29 days (primary endpoint, see Table 2). For the population subset of patients with severe erythema at baseline Day 1 (i.e. subjects with CEA or PSA grade of 4) which represented 26% of the randomised subjects, the results on the primary endpoint on Day 29 were similar to those results observed in the overall population (see Table 3) and were statistically significant for both studies combined (p=0.003). In addition, for the overall population, Locular demonstrated statistical superiority (p<0.001) over vehicle gel with respect to rapid initial onset of a clinically meaningful effect (1-Grade Composite Success for CEA and PSA) after the first application at 30 minutes on Day 1(secondary endpoint 27.9% vs. 6.9% for Study 1, 28.4% vs. 4.8% for Study 2), and to achievement of a clinically meaningful effect (1-Grade Composite Success for CEA and PSA) on Day 29 (tertiary endpoint, see Table 4).
CEA and PSA were defined as follows:
CEA: Clinician Erythema Assessment: 0=Clear skin with no signs of erythema, 1=Almost clear; slight redness, 2=Mild erythema; definite redness, 3=Moderate erythema+ marked redness and 4=Severe erythema+ fiery redness
PSA: Patient Self-Assessment: 0=No redness, 1=Very mild redness, 2=Mild redness, 3=Moderate redness and 4=Severe redness
Table 2: Percentage of subjects with a 2-grade improvement in both CEA and PSA
| Success day 29 | Study 1 | Study 2 | ||
| Locular Gel n=127 | Vehicle Gel n=128 | Locular Gel n=142 | Vehicle Gel n=142 | |
| 3 hours after application | 31.5% | 10.9% | 25.4% | 9.2% |
| 6 hours after application | 30.7% | 9.4% | 25.4% | 9.2% |
| 9 hours after application | 26.0% | 10.2% | 17.6% | 10.6% |
| 12 hours after application | 22.8% | 8.6% | 21.1% | 9.9% |
| Day 29 p-value | <0.001 | - | <0.001 | - |
Table 3: Percentage of subjects with severe erythema at baseline Day 1 (CEA or PSA grade 4) with 2-grade improvement in both CEA and PSA
| Success day 29 | Study 1 + Study 2 | |
| Locular Gel n=79 | Vehicle Gel n=63 | |
| 3 hours after application | 22.8% | 9.5% |
| 6 hours after application | 26.6% | 7.9% |
| 9 hours after application | 20.3% | 11.1% |
| 12 hours after application | 21.5% | 4.8% |
| Day 29 p-value | 0.003 | - |
Table 4: Percentage of subjects with a 1-grade improvement in both CEA and PSA
| Success Day 29 | Study 1 | Study 2 | ||
| Locular Gel n=127 | Vehicle Gel n=128 | Locular Gel n=142 | Vehicle Gel n=142 | |
| 3 hours after application | 70.9% | 32.8% | 71.1% | 40.1% |
| 6 hours after application | 69.3% | 32.0% | 64.8% | 43.0% |
| 9 hours after application | 63.8% | 29.7% | 66.9% | 39.4% |
| 12 hours after application | 56.7% | 30.5% | 53.5% | 40.1% |
| Day 29 p-value | <0.001 | - | <0.001 | - |
No clinically meaningful trends with respect to tachyphylaxis or rebound effects (worsening of baseline erythema after cessation of treatment) were observed with use of Locular for 29 days.
The results from a long term open label study in 449 patients, with continuous treatment for up to one year, confirmed that chronic use of Locular is safe and effective. Daily reductions in erythema for the first month of use (as measured with the CEA and PSA scales) were similar to those observed in the controlled trials, and those reductions were achievable for up to 12 months with no apparent loss of effect over time. The overall frequencies of adverse reactions in this study are reflected in Table 1 above, with the highest rates occurring in the first 29 days of use. No adverse reactions had an increase in frequency over time, and there was no evidence that long-term use of Locular conveyed an increased risk of occurrence of any specific type of adverse reaction.
Concomitant use of Locular with other medicinal products for the treatment of inflammatory lesions of rosacea has not been systematically investigated. However, in the long term open label study, the efficacy and safety of Locular, as described above, was not affected by the concomitant use of cosmetics or other medicinal products (e.g. topical metronidazole, topical azelaic acid, and oral tetracyclines including low dose doxycycline) for the treatment of inflammatory lesions of rosacea in the concerned subpopulation (131/449 patients in the study used concomitant rosacea medicinal product).
Paediatric population
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Absorption
The absorption of brimonidine from Locular was evaluated in a clinical study in 24 adult subjects with facial erythema of rosacea. All enrolled subjects received a single-day ocular administration of a 0.2% eye drops solution of brimonidine followed by a once daily cutaneous application of Locular for 29 days (intra-individual comparison of systemic exposure). On Day 1 of the study, all subjects received 1 drop of the 0.2% eye drops solution in each eye, every 8 hours over a 24-hour period (3 doses in total).
After repeated cutaneous application of Locular on facial skin, no drug accumulation in plasma was observed throughout the treatment duration: the highest mean (± standard deviation) plasma maximum concentration (Cmax) and area under the concentration-time curve from 0 to 24 hours (AUC0-24hr) were 46 ± 62 pg/mL and 417 ± 264 pg.hr/mL respectively. These levels are significantly lower (2-fold) than those observed following single-day ocular administration of a 0.2% eye drops solution of brimonidine.
Distribution
The protein binding of brimonidine has not been studied.
Biotransformation
Brimonidine is extensively metabolised by the liver.
Elimination
Urinary excretion is the major route of elimination of brimonidine and its metabolites.
Absorption
After ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked within 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours.
Distribution
The protein binding of brimonidine has not been studied.
Metabolism
In humans, brimonidine is extensively metabolized by the liver.
Excretion
Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Not applicable.
No special requirements.
However, we will provide data for each active ingredient
