Onreltea: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Onreltea - Product Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Rosacea
Class: Miscellaneous agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: brimonidine tartrate, carbomer, glycerol, methylparahydroxybenzoate, phenoxyethanol, propylene glycol, purified water, titanium dioxide, sodium hydroxide

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Nonmedicinal Ingredients
Topical brimonidine gel
/ 0.33% w/w (as
abrimonidine tartrate)
none*

* For a complete listing see Dosage Forms, Composition and Packaging section of the product monograph.

Indications and Clinical Use

ONRELTEA (brimonidine) Gel, 0.33% is indicated for:

  • the topical treatment of facial erythema of rosacea in adults 18 years of age or older.

Geriatrics (> 65 Years of Age)

104 elderly patients (>65 years of age) were included in Phase 3 clinical trials with ONRELTEA. No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

Pediatrics (< 18 Years of Age)

ONRELTEA is contraindicated in children less than 2 years of age.

ONRELTEA is not recommended for children between 2 and 18 years of age.

(see CONTRAINDICATIONS, WARNING and PRECAUTIONS).

Safety and effectiveness in pediatric patients have not been established.

Contraindications

ONRELTEA (brimonidine) Gel, 0.33% is contraindicated in:

  • Patients who are hypersensitive to brimonidine tartrate or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
  • Neonates and infants (under the age of 2 years).

Warnings and Precautions

General

Not for oral, ophthalmic, or intravaginal use.

ONRELTEA (brimonidine) Gel, 0.33% should not be applied on irritated skin or open wounds. In case of severe irritation or contact allergy, the treatment with ONRELTEA should be discontinued and the patient should obtain medical advice.

Erythema and Flushing

The effect of ONRELTEA 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 ONRELTEA topical gel varied, ranging from approximately 30 minutes to several hours.

In the majority of these cases, erythema and flushing resolved after discontinuation of ONRELTEA topical gel.

In case worsening of erythema occurs, ONRELTEA 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 ONRELTEA 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 dose and frequency of application: once daily use in a thin layer.

Cardiovascular

Concomitant use of systemic Alpha-2 adrenergic agonists may potentiate the undesirable effects of this class. Therefore, Alpha-2 adrenergic agonists should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thrombangiitis obliterans, scleroderma, or Sjögren’s syndrome.

Alpha-2 adrenergic agonists can lower blood pressure and should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease.

Hepatic/Biliary/Pancreatic

ONRELTEA has not been studied in patients with renal or hepatic impairment; caution should be used in treating such patients.

Serious Adverse Reactions Following Accidental Ingestion of ONRELTEA topical gel

Two young children of a subject in a clinical trial experienced serious adverse reactions following accidental ingestion of ONRELTEA topical gel. Adverse reactions experienced by one or both children included lethargy, respiratory distress with apneic episodes (requiring intubation), sinus bradycardia, confusion, psychomotor hyperactivity, and diaphoresis. Both children were hospitalized overnight and discharged the following day without sequelae.

Special Populations

Pregnant Women

Brimonidine tartrate was not teratogenic when given at oral doses up to 2.5 mg/kg in pregnant rats and 5 mg/kg in pregnant rabbits during gestation. In reproductive and developmental toxicity studies performed in rats at oral doses up to 1 mg/kg/day, there was no evidence of impaired fertility or pre and post-natal development or harm to the fetus.

There are no adequate and well-controlled studies with the use of ONRELTEA in pregnant women. Because animal reproduction studies are not always predictive of human response, ONRELTEA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Women

It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate and some of its metabolites have been shown to be excreted in milk of lactating rats. Because of the potential for serious adverse reactions from ONRELTEA 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.

Pediatrics (<18 Years of Age)

ONRELTEA is contraindicated in children less than 2 years of age because of serious systemic safety risks(see CONTRAINDICATIONS). Safety concerns related to the systemic absorption of brimonidine have also been identified for the age group 2 to 12 years.

ONRELTEA is not recommended in children and adolescents between 2 and 18 years of age.

Safety and effectiveness in pediatric patients (<18 years of age) have not been established. Keep ONRELTEA topical gel out of reach of children.

Geriatrics (>65 Years of Age)

104 elderly patients (>65 years of age) were included in Phase 3 clinical trials with ONRELTEA.

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

Adverse Reactions

Adverse Drug Reaction Overview

During clinical trials, 1210 subjects were exposed to ONRELTEA (brimonidine) Gel, 0.33%. A total of 833 subjects were treated for facial erythema of rosacea, 330 of those were treated once daily for 29 days in a vehicle-controlled trial.

The most commonly (i.e. ≥1%) reported adverse drug reactions are erythema, pruritus, flushing and skin burning sensation, all occurring in 1.2 to 3.3% of patients. These were usually transient, mild to moderate in severity, and usually did not require discontinuation of treatment.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse events that occurred in controlled clinical trials in at least 1% of subjects treated withONRELTEA and the corresponding rates reported in subjects treated with the vehicle gel are presented in Table 1.

Table 1: Commonly Reported Adverse Drug Reactions Reported in Controlled Clinical Trials
System Organ Class / Preferred Term ONRELTEA
(N = 330)
n (%)
Vehicle Gel
(N = 331)
n (%)
Patients with at least one AE, Number (%) of Patients
Skin And Subcutaneous Tissue Disorders
Erythema
Pruritus
Skin burning sensation
Vascular Disorders
Flushing
39 (11.8)
32 (9.7)

11 (3.3)
8 (2.4)
4 (1.2)
4 (1.2)
4 (1.2)
29 (8.8)
22 (6.6)

3 (0.9)
6 (1.8)
2 (0.6)
1 (0.3)
0

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Eye disorders: eyelid oedema

Gastrointestinal: dry mouth

General disorders and administration site conditions: feeling hot, coldness of skin

Metabolism and nutrition disorders: alcohol induced flushing

Nervous system disorders: headache, paraesthesia

Respiratory, thoracic and mediastinal disorders: nasal congestion, nasal stingingSkin and subcutaneous tissue disorders:, acne, dermatitis, allergic contact dermatitis, contact dermatitis, dry skin, pain of skin, rash papular, rosacea, skin discomfort, skin irritation, skin warm, face swelling, urticaria

Most local adverse reactions were rated as mild to moderate and they are not affected by age, race or gender.

Post-Market Adverse Drug Reactions

Aggravated erythema, flushing and skin burning sensation were reported with a common frequency during the post-marketing period (see Warnings and Precautions General).Swelling face and urticaria were reported with an uncommon frequency during the post-marketing period.

Drug Intrractions

Overview

No specific drug-drug interaction studies have been conducted with ONRELTEA (brimonidine) Gel, 0.33%.

Cns Depressants

The possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side- effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

Although specific drug-drug interactions studies have not been conducted with ONRELTEA, the possibility of an additive or potentiating effect with Central Nervous System depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

No data on the level of circulating catecholamines after ONRELTEA administration are available. Caution, however, is advised in patients taking medications which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine. Caution is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with alpha adrenergic receptor agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor (e.g. isoprenaline, prazosin).

Caution should be taken in using concomitantly with other systemic alpha adrenergic receptor agonists.

Anti-hypertensives/Cardiac Glycosides

Alpha-2 agonists, as a class, may reduce blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised.

Drug-Food Interactions

ONRELTEA is for topical use only. Drug-food interactions have not been studied.

Drug-Herb Interactions

Interactions with herbal products have not been studied.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been studied.

Dosage and Administration

Dosing Considerations

ONRELTEA (brimonidine) Gel, 0.33% should not be applied on irritated skin or open wounds. In case of severe irritation or contact allergy, the treatment with ONRELTEA should be discontinued and the patient should obtain medical advice.

Not for oral, ophthalmic, or intravaginal use.

For many patients, this product should start to relieve the facial redness within 30 minutes with maximum effect at about 3 hours. The patient should be informed that if the product does not improve the symptom within 5 days, to contact the doctor.

Recommended Dose and Dosage Adjustment

Once daily application.

Five small pea size amounts, estimated to be no more than 1 g in total weight, is the maximum daily recommended dose.

Administration

Once daily, cutaneous application of a small pea size amount of product to each of the five areas of the face (i.e., forehead, chin, nose, each cheek) avoiding the eyes and eyelids, lips, mouth, membrane of the inner nose. ONRELTEA should be applied smoothly and evenly across all application areas.

Hands should be washed immediately after applying ONRELTEA.

Cosmetics may be applied after the application of ONRELTEA.

Overdosage

No information is available on overdose in adults with ONRELTEA (brimonidine) Gel, 0.33%.

Oral overdoses of other alpha-2 adrenergic agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.

Serious adverse effects following inadvertent ingestion of ONRELTEA by the two young children of one clinical study subject were reported. The children experienced symptoms consistent with previously reported oral overdoses of alpha-2 agonist in young children. Both children were reported to have made a full recovery within 24 hours.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Brimonidine is a highly selective alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenergic receptor than the alpha-1 adrenergic receptor.

The subcutaneous vasoconstrictive effect of alpha-2 adrenergic receptor stimulation is considered to be the basis of the clinical efficacy of brimonidine for once daily cutaneous treatment of facial erythema of rosacea in adult patients.

Pharmacodynamics

Cutaneous facial application of a highly selective alpha-2 adrenergic receptor agonist reduces erythema through direct cutaneous vasoconstriction.

Pharmacokinetics

Absorption

The absorption of brimonidine from ONRELTEA (brimonidine), 0.33% Gel was evaluated in a clinical study in 24 adult subjects with facial erythema associated with rosacea. All enrolled subjects received a single-day ocular administration of a 0.2% ophthalmic solution of brimonidine followed by a once daily topical application of ONRELTEA for 29 days (intra-individual comparison of systemic exposure). After repeated topical application of ONRELTEA 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 than those observed following TID ocular administration of a 0.2% eye drops solution of brimonidine tartrate.

Distribution

The protein binding of brimonidine has not been studied.

Metabolism

Brimonidine is extensively metabolized by the liver.

Excretion

Urinary excretion is the major route of elimination of brimonidine and its metabolites.

Special Populations and Conditions

Studies to assess the effect of ONRELTEA in special populations were not conducted. Because of the very low systemic exposures observed in clinical studies, no new safety issues would be anticipated for ONRELTEA in special patient populations.

Storage and Stability

Store at room temperature (15°C to 30°C). Protect from freezing.

Special Handling Instructions

Hands should be washed immediately after applying ONRELTEA (brimonidine) Gel, 0.33%. Access to ONRELTEA by children or pets should be prevented during usage, disposal and storage of the product.

Special Handling Instructions

Hands should be washed immediately after applying ONRELTEA (brimonidine) Gel, 0.33%. Access to ONRELTEA by children or pets should be prevented during usage, disposal and storage of the product.

Dosage Forms, Composition and Packaging

ONRELTEA (brimonidine) Gel, 0.33% is available as a white to light yellow opaque aqueous gel. Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base. The non-medicinal ingredients are: carbomer, glycerol, methylparahydroxybenzoate, phenoxyethanol, propylene glycol, purified water, titanium dioxide, sodium hydroxide.

ONRELTEA is commercially available in laminated plastic tubes with a high density polyethylene (HDPE) head and polypropylene (PP) child resistant closure in a pack size of 30 g.

Physician samples are available in laminated plastic tubes with a high density polyethylene (HDPE) head and polypropylene (PP) non-child resistant closure in a pack size of 2 g.