Brimonidine tartrate is a relatively selective alpha-2 adrenergic receptor agonist that, in radioligand binding assays and in functional assays, is approximately 1000 times more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor. This selectivity results in the absence of vasoconstriction in microvessels associated with human retinal xenografts. Topical administration of brimonidine decreases intraocular pressure (IOP) in humans. When used as directed, brimonidine tartrate ophthalmic solutions reduce elevated IOP with minimal effect on cardiovascular parameters. Brimonidine tartrate has a rapid onset of action, with the peak ocular hypotensive effect occurring at approximately two hours post-dosing. The duration of effect is 12 hours or greater. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. Brimonidine tartrate ophthalmic solution 0.15% (preserved with Purite(r)) lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow.

Pharmacodynamics

Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r))1 has no effect on pulmonary function or exercise-induced tachycardia. The cardiovascular effects of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) during exercise in normal volunteers were found to be limited to a slight suppression of systolic blood pressure, which was clinically insignificant, during the recovery period following a treadmill test.

Pharmacokinetics

After ocular administration of Brimonidine-PuriteTM ophthalmic solution 0.1% or 0.2% (brimonidine tartrate 0.1% or 0.2% with Purite(r)), plasma concentrations peaked within 0.5 to 2.5 hours, and declined with a systemic half-life of approximately 2 hours.

1 Purite(r) (oxychloro complex) solution is comprised of predominantly sodium chlorite. In humans, brimonidine is eliminated rapidly via extensive systemic metabolism; there is no marked systemic accumulation after multiple dosing. It is metabolized primarily by the liver. Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours, with 74% found in the urine.

Clinical Studies

Brimonidine tartrate lowers intraocular pressure with minimal effect on cardiovascular parameters (heart rate, systolic and diastolic blood pressure) and no apparent effect on pulmonary parameters (spirometry, respiratory rate). Two clinical studies (n=1,147) lasting for twelve months were conducted to evaluate the safety, efficacy, and acceptability of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) and 0.2% Brimonidine-PuriteTM compared with brimonidine tartrate ophthalmic solution 0.2% (preserved with benzalkonium chloride), administered three-times-daily in patients with glaucoma or ocular hypertension. The intraocular pressure values for the Baseline and Month-12 time points using brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) and 0.2% (with benzalkonium chloride) are summarized in the table below.

a = 95% confidence interval for difference between brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) and 0.2% (with benzalkonium chloride) concentrations

There was no statistical significance between brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) and 0.2% (with benzalkonium chloride) for within group analysis of changes from baseline using a paired t-test (at all time points the p-value was <0.001) Efficacy analyses from these two clinical trials indicated that brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) is non-inferior to brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride) and effectively lowered IOP in patients with glaucoma or ocular hypertension (mean values of at least 2.6 mm Hg at trough, and at least 4.3 mm Hg at peak) over the twelve months of the study. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) was well tolerated, rated as comfortable by the majority of patients, and provided a superior safety profile when compared with brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride). Among the most commonly reported adverse events (>=3.9% incidence in the brimonidine tartrate ophthalmic solution 0.15% [with Purite(r)] group), the frequency of reports were generally fewer than with brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride). There was a significantly smaller percentage of patients who experienced allergic conjunctivitis, oral dryness, asthenia, or somnolence in the brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) group. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) was the lowest effective dose of brimonidine tartrate efficacy with the most favorable safety and tolerability profile.

CONTRAINDICATIONS

APO-BRIMONIDINE P (brimonidine tartrate) ophthalmic solution, 0.15% is contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. It is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy.

WARNINGS

The use of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in paediatric patients is currently not recommended. ADVERSE REACTIONS

Several serious adverse reactions have been reported in association with the administration of brimonidine tartrate ophthalmic solution 0.2% to infants in the age range of 28 days to 3 months. (See

PRECAUTIONS

General

Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) should be used with caution in patients with known hypersensitivity to other alpha-adrenoceptor agonists.

Use in Patients with Special Conditions

Although brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) had minimal effect on blood pressure and heart rate of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) has not been studied in patients with hepatic or renal impairment; caution should be exercised in treating such patients. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Drug Interactions

Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)), the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) did not have clinically significant effects on pulse and blood pressure in chronic clinical studies. However, since alpha-agonists, as a class, may reduce pulse and blood pressure, caution in the concomitant use of drugs such as beta-blockers (ophthalmic and/or systemic), antihypertensives and/or cardiac glycosides is advised. Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) can lead to an interference in IOP lowering effect. No data are available on the level of circulating catecholamines after brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) is instilled. Caution, however, is advised inpatients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No compound-related carcinogenic effects were observed in 21 month and 2 year studies in mice and rats given oral doses of 2.5 mg base/kg/day and 1.0 mg base/kg/day of brimonidine tartrate, respectively. These doses achieved 106 and 145 times, respectively, the plasma drug concentration estimated in humans treated with one drop of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) into both eyes three times per day. Brimonidine was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, host-mediated assay, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, cytogenic studies in mice and dominant lethal assay.

Use in Pregnancy (see Reproduction and Teratology section)

Teratogenicity studies showed no adverse effects in rats and rabbits when oral doses (1.65 mg base/kg/day and 3.33 mg base/kg/day of brimonidine tartrate) were administered during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. These doses achieved AUC values 258- and 17-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) given as one drop in both eyes three times per day. There are no studies of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in pregnant women, however in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent (ratio of drug-related material in fetal:matemal blood=0.1 - 0.3). Drug-derived material was eliminated from fetal tissues by 24 hours post-dose. Brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) 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 is excreted in human milk, although in animal studies, brimonidine has been shown to be excreted in breast milk. During treatment with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)), 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.

Use in Paediatrics

The use of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in paediatric patients is currently not recommended.

reported in association with the administration of brimonidine tartrate ophthalmic solution 0.2% to infants in the age range of 28 days to 3 months. (See ADVERSE REACTIONS section).

Information to be Provided to the Patient by the Physician

APO-BRIMONIDINE P (brimonidine tartrate) ophthalmic solution 0.15, as with other similar medications, can potentially cause fatigue and/or drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental alertness. Patients should be advised to keep the dropper tip of the bottle from touching the eye or other surrounding structures, because of the potential for bacterial contamination. Contact lenses should be removed prior to instillation of APO-BRIMONIDINE P Ophthalmic Solution, 0.15% and may be reinserted 15 minutes after its instillation.

ADVERSE REACTIONS

In clinical studies the most frequently reported adverse reactions (>1%) classified as treatment- related from the 12 month Phase III controlled clinical studies for patients (n=380) who received brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) were: conjunctival hyperemia (18.2%), allergic conjunctivitis (9.2%), eye pruritus (8.2%), visual disturbance (6.1%), conjunctival folliculosis (5.5%), oral dryness (5.3%), burning sensation in the eye (5.3%), eye dryness (2.9%), foreign body sensation (2.9%), epiphora (2.6%), headache (2.4%), eyelid edema (2.1%), eye pain (1.8%), asthenia (1.6%), blepharitis (1.6%), erythema eyelid (1.6%), irritation eye (1.6%), ocular stinging sensation (1.6%), photophobia (1.6%), conjunctival edema (1.3%), eye discharge (1.3%), follicular conjunctivitis (1.3%), superficial punctate keratitis (1.3%), rhinitis (1.1%), visual acuity worsened (1.1%).

Serious Reports of Adverse Reactions in Paediatric Patients

Several serious adverse reactions have been reported in association with the administration of brimonidine tartrate ophthalmic solution 0.2% to infants in the age range of 28 days to 3 months. These reactions included: bradycardia, hypotension, hypothermia, hypotonia, apnea, dyspnoea, hypoventilation, cyanosis and lethargy resulting in hospitalisation. Upon discontinuation of brimonidine tartrate ophthalmic solution 0.2% the infants recovered without sequelae.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No data are available on overdosage of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in humans. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. Evacuation of the stomach should be considered during the first few hours after an overdosage.

DOSAGE AND ADMINISTRATION

The recommended dose is one drop of APO-BRIMONIDINE P (brimonidine tartrate) Ophthalmic Solution, 0.15% in the affected eye(s) three times daily, approximately 8 hours apart.

PHARMACEUTICAL INFORMATION

Drug Substance

Common name: Brimonidine tartrate Chemical name: Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate Structural formula:

Molecular weight: 442.2 Description: Brimonidine tartrate is an off-white, pale yellow to pale pink powder, with a melting point range of 202 - 210degC. It is water soluble (34 mg/mL) and soluble in DMSO (>60 mg/mL), slightly soluble in propylene glycol (~1.0 mg/mL), and very slightly soluble in ethanol (0.6 mg/mL) and acetone (<0.2 mg/mL). The pH of a 1% solution of brimonidine tartrate in water is 3.5 at room temperature. A pKa value of 7.78 +- 0.05 has been determined.

Composition

Each mL of APO-BRIMONIDINE P Ophthalmic Solution, 0.15% contains brimonidine tartrate 1.5 mg with the following non-medicinal ingredients: Sodium Chlorite 25% w/v Solution Stabilized (as preservative), boric acid, calcium chloride dihydrate, carboxymethylcellulose sodium, magnesium chloride, potassium chloride, sodium borate, sodium chloride, water for injection and hydrochloric acid or sodium hydroxide to adjust the pH.

Stability and Storage Recommendations

APO-BRIMONIDINE P Ophthalmic Solution, 0.15% should be stored at room temperature between 15degC to 30degC (59degF - 86degF). Discard unused solution at the end of treatment.

AVAILABILITY OF DOSAGE FORMS

APO-BRIMONIDINE P (brimonidine tartrate) Ophthalmic Solution, 0.15% is supplied in an 11 mL white opaque LDPE ophthalmic bottle with a white translucent LDPE ophthalmic dropper and a white opaque ophthalmic HDPE copolymer cap with sealing tape.

INFORMATION FOR THE CONSUMER

APO-BRIMONIDINE P Ophthalmic Solution, 0.15%

Do not allow the dropper tip of the bottle to touch the eye or other surrounding structures, because this could contaminate the tip with common bacteria known to cause eye infections. Serious damage to the eye with subsequent loss of vision may result if you use eye drop solutions that have become contaminated. If you experience any type of eye condition or have surgery, immediately seek your doctor's advice concerning the continued use of the bottle you are using.

NOTE: If you forget to apply your eye drops at your normal time, simply apply them as soon as you remember. Then go back to the original schedule as directed by your doctor. Don't try to catch up on missed drops by applying more than one dose at a time.

Patients Wearing Soft Contact Lenses:

Lenses should be removed prior to application of APO-BRIMONIDINE P 0.15% and not re- inserted earlier than 15 minutes after use.

Side Effects:

APO-BRIMONIDINE P 0.15% may cause drowsiness and fatigue in some patients. Caution should be exercised when engaged in activities where mental alertness is required. Some common side effects which may occur include red eyes, swelling of the eyelid, tearing, itchy eyes, blurred vision, dry mouth and a burning feeling in the eye. If these persist or cause you concern, consult your doctor.

PHARMACOLOGY

Animal Pharmacology

Receptor binding and functional studies have characterized brimonidine as a potent and selective alpha-2-adrenoceptor agonist. As indicated in Table 1, brimonidine is notably more alpha-2 adrenoceptor selective than clonidine and p-aminoclonidine in both radioligand binding and functional assays.

*Mean +- SEM; 'N' is noted in parentheses. a[3H]Prazosin in human cerebral cortex. b[3H]Rauwolscine binding in HT-29 cells. CContraction of isolated rabbit aorta.

lnhibition of electrically induced contractions in the isolated rabbit vas deferens.

The ocular hypotensive effect of brimonidine has been demonstrated in normotensive rabbits, cats, and monkeys, as well as ocular hypertensive rabbits and monkeys. This effect is maintained following six months of chronic administration to albino rabbits (Table 2).

Mean decrease in treated eye IOP (mm Hg) from vehicle-treated control at 2 hr following the AM dose.

* Significantly different from vehicle-treated animals (p<0.05) for treated eye.

Twenty-eight days of BID dosing of brimonidine tartrate 0.5% to rabbits and monkeys demonstrated that monkeys experience a significantly diminished trough ocular hypotensive effect on chronic dosing. In rabbits, the trough IOP effect was unaltered, however, the peak effect significantly increased with this dosing regimen (confirmed also by 6 month experiments - see Table 2). The mechanism of action for the ocular hypotensive effect of brimonidine in rabbits and monkeys is predominantly the suppression of aqueous humor production. Trabecular outflow was not found to be affected in monkeys. In rabbits, a secondary mechanism of action includes an enhancement of uveoscleral outflow. Investigational studies have demonstrated that topically administered brimonidine stimulates a peripheral alpha-2 adrenoreptor to lower IOP in rabbits. SKF 104078, the selective postjunctional alpha-2 receptor antagonist, did not block the ocular hypotensive effects of brimonidine in rabbits, suggesting that the vascular postjunctional alpha-2 adrenoceptor is not involved in the IOP response in this species. The data in monkeys suggest that the IOP and cardiovascular responses to brimonidine are mediated by an imidazoline receptor located in the central nervous system (CNS). The miotic response to brimonidine which occurs in monkeys is mediated by an alpha-2 adrenoceptor. When the action of brimonidine as a neuroprotective agent was evaluated in in vitro and in vivo pharmacological studies in rat, no deleterious effects on the optic nerve were observed.

Human Pharmacology

The effect of brimonidine on aqueous humour dynamics was determined in 21 ocular hypertensive patients. Measurements were made at baseline and

following one week (Day 8) of twice daily application of one drop of brimonidine tartrate 0.2% to one eye and vehicle to the fellow eye, in a double-blind fashion. Aqueous flow (Fa, mL/min) and outflow capacity (Cfl, mL/min/mmHg) were determined using a fluorophotometric technique. Intraocular pressure (IOP, mmHg), tonographic outflow facility (Cton, mL/min/mmHg), and episcleral venous pressure (Pev, mmHg) were also measured. Uveoscleral outflow (mL/min) by fluorophotometry (Fufl) or tonography (Futon) was calculated from Cfl or Cton values, respectively. The results of this study (mean+-SEM) are reported in Table 3. They indicate that brimonidine reduces IOP in humans by decreasing aqueous inflow and increasing uveoscleral outflow.

In short-term studies (up to four days) in normal healthy volunteers, brimonidine tartrate ophthalmic solutions preserved with benzalkonium chloride lowered IOP (intraocular pressure) significantly better than vehicle at all concentrations tested (0.02-0.5%) and was found to be safe and comfortable. At these concentrations, the peak effect on IOP was observed between one and four hours post-instillation. The greatest reduction in IOP was dose- related, reaching a maximal decrease from baseline of up to 40% with brimonidine tartrate 0.5%. In the morning (12 hours after the evening instillation), the 0.08% and 0.2% concentrations reached a maximal IOP lowering effect following two days of BID dosing. This was observed with the 0.5% concentration, however, 12 hours after the first instillation. Conjunctival blanching was observed primarily at the 0.35% and 0.5% concentrations, and was generally mild or moderate in nature. There was a significantly greater incidence of dry eye seen only with brimonidine tartrate 0.5% as compared to vehicle, although this finding was also reported at the lower concentrations. The overall mean decrease in pupil size and systolic blood pressure was generally greater with brimonidine 0.2% and 0.5% than with vehicle. This change in systolic blood pressure was not judged to be clinically significant. Heart rate, diastolic blood pressure, visual acuity and cup-disc ratio did not appear to be significantly affected by brimonidine treatment (as compared to vehicle). Additionally, at the concentrations tested in these healthy volunteer studies, a contralateral effect of brimonidine was not observed.

When evaluated in open-angle glaucoma and ocular hypertensive patients at concentrations of 0.08%, 0.2% and 0.5% for one month (BID), brimonidine tartrate was found to be both efficacious and safe. All concentrations tested were significantly more effective than vehicle in lowering elevated IOP. The two higher concentrations of brimonidine tartrate were also more effective than the 0.08% concentration. Brimonidine tartrate 0.5%, however, was not any more effective than 0.2% for long-term treatment. The peak effect on IOP occurred at two hours for brimonidine tartrate 0.08%, 0.2%, and 0.5%. The greatest decrease in IOP was dose-related, with a maximum reduction of 27% from baseline with brimonidine tartrate 0.2%, and 31% from baseline with brimonidine tartrate 0.5%. Brimonidine tartrate 0.5% was associated with a greater incidence of side effects than brimonidine tartrate 0.2% and 0.08%, including blurring, foreign body sensation, fatigue and drowsiness. Dry mouth was seen more often in all active treatment groups than in the vehicle group. This event was also seen at a higher incidence with brimonidine tartrate 0.5% than with brimonidine tartrate 0.08%. Although heart rate did not appear to be significantly affected by brimonidine treatment, diurnal measurements of blood pressure indicated that brimonidine tartrate 0.5% was associated with a greater decrease than was vehicle or the lower brimonidine strengths. The mean blood pressure decreases observed were not considered to be clinically significant. Two 1-month, dose-response studies (n=222) were conducted to evaluate the efficacy and safety of Brimonidine-Purite(tm), dosed either twice-daily or three-times-daily, compared with brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride), Timoptic(r), and vehicle. Brimonidine-Purite(tm) 0.1% and 0.2% lowered IOP significantly, compared to vehicle when dosed twice or three times daily. However, Brimonidine-Purite(tm) 0.1% was less effective than Brimonidine-Purite(tm) 0.2%, brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride), or Timoptic(r), regardless of its dosing regimen. Both Brimonidine- Purite(tm) 0.1% and 0.2% demonstrated acceptable safety profiles.

Systemic Pharmacokinetics

Systemic absorption of brimonidine after ocular administration of a single dose (both eyes) of brimonidine tartrate 0.08%, 0.2% and 0.5% to healthy volunteers, produced dose-dependent increases in Cmax and AUC. AUC increased proportionally with dose between the 0.08% and 0.2% doses; the increase in AUC of the 0.5% dose was less than proportional with the increase in dose. Following the 0.5% dose, plasma Cmax and AUC0-[?] were approximately 0.1 ng/mL and 0.5 ng *hr/mL, respectively. The mean Tmax was 2-3 hours for all concentrations tested in this study. In general, plasma concentrations declined to undetectable levels by 12 hours post- dose. The apparent plasma t1/2 ranged from 2 to 5 hours (mean=3.3 hours). Plasma concentration-time profiles were similar for both young and elderly healthy volunteers following ocular instillation of a single dose of brimonidine tartrate 0.2%, although the elderly subjects showed a tendency to have a slightly greater systemic exposure to brimonidine. Steady state concentrations were reached by day 7 of multiple dosing (both eyes, BID) in young (23-39 years) subjects. Twice daily ocular dosing for 10 days did not change the systemic absorption and disposition parameters of brimonidine in young subjects. The mean Cmax was 0.0585 ng/mL and mean AUC0-12 was 0.309 ng *hr/mL after multiple dosing. There was a slight systemic drug accumulation after repeated dosing (accumulation factor: 1.4), consistent with an apparent half-life of 3 hours. Beyond 12 hours after the final dose, plasma concentrations were undetectable or approached the limit of quantitation. Systolic and diastolic blood pressures were generally lowered by brimonidine tartrate administration. These decreases in blood pressure tended to be slightly greater among the elderly subjects than among the young subjects. Plasma brimonidine concentrations and serum glucose concentrations during brimonidine tartrate treatment TID were investigated in a single-center, randomized, double-masked, vehicle-controlled, parallel study of 0.1% and 0.2% brimonidine tartrate ophthalmic solution preserved with Purite(r) in healthy subjects. Concentration-time profiles of brimonidine were assessed on days 1 and 7. Plasma brimonidine concentrations were proportional to dose, and during treatment with 0.2% brimonidine tartrate ophthalmic solution preserved with Purite(r), were comparable to those measured during treatment with brimonidine tartrate ophthalmic solution preserved with benzalkonium chloride (brimonidine tartrate ophthalmic solution 0.2%). Plasma Cmax during TID treatment with brimonidine tartrate ophthalmic solution 0.15% (preserved with Purite(r)) are expected to be approximately 47.4 pg/mL, compared to 58.5 pg/mL during BID treatment with brimonidine tartrate ophthalmic solution 0.2% (with benzalkonium chloride). Systemic accumulation was minimal. Brimonidine did not affect systemic glucose disposition or serum glucose levels.

TOXICOLOGY

Acute Toxicity

The acute median lethal dose (LD50) or minimum lethal dose (MLD) values of brimonidine were evaluated in mice, rats, rabbits, and dogs by oral and intravenous (i.v.) administration. The LD50 or MLD values for each study are listed below:

* The doses are expressed as the base except in the mouse and rat MLD data, where they are expressed as

* *The data from additional single dose oral studies of 0.2% and 0.5% solutions of brimonidine tartrate in mice and rats showed that the oral MLD is greater than 10 mg/kg.

The most frequently observed clinical signs in the acute/single dose toxicity studies were primarily due to the exaggerated pharmacological hypotensive effect of the compound. These signs included: sedation, ataxia, prostration, ptosis, reduced/loss of blink reflex, opacification of the cornea, hypotension, bradycardia, hypothermia, respiratory depression, respiratory arrest and circulatory collapse. The ocular changes were seen only after doses at or above the minimum lethal dose.

Long-term Toxicity

Long-term toxicity studies with brimonidine tartrate in various concentrations using mice, rats, rabbits, dogs and monkeys were conducted for durations of up to one year. The most notable effects seen in these studies were related to the known pharmacological effect of brimonidine. Brimonidine was administered in repeated oral doses to mice (3 studies -12 to 13 weeks), rats (6 studies - 6 days to 1 year), dogs (2 studies - 4 to 14 weeks) and monkeys (2 studies - 1 year each). It was also administered occularly to rabbits (2 studies - 1 and 6 months) and dogs (1 study - 4 weeks) and monkeys (1 study - 1 year). There were no observable adverse effects in oral dosing of mice at approximately 145 times the recommended ocular human dose, rats at approximately 70 times the recommended ocular human dose, rabbits at approximately 22 times the recommended ocular human dose, dogs at approximately 50 times the recommended ocular human dose, and monkeys at approximately 30 times the recommended ocular human dose. Dosage levels of approximately 295 times greater than those recommended for human ocular use showed toxic effects that were consistent with the pharmacological class of the compound. Chronic oral dosing studies were performed at extreme levels of approximately 2650 times the recommended human ocular dose. At these extreme doses, mice showed goblet cell hyperplasia and depletion in the rectum and colon, hypertrophy of the tunica muscularis of small and large intestine, and hyperplasia of the non-glandular epithelium of the stomach. Rats dosed orally at approximately 1330 times the human ocular dose, showed thickening of muscularis mucosa of small intestine, and a dose related incidence of illeal intussusception was observed in all rats, but no associated lesions or morphological changes were observed. Evidence of toxicity characterised by decreased body weight gain and/or decreased food consumption was often seen at the higher oral doses in the mouse, rat and monkey. The most notable effects seen in the subacute studies was an exaggerated pharmacological effect characterised by sedation, ataxia, hypoactivity, ptosis, decreased muscle tone, hypotension and bradycardia. There were no observable adverse effects in ocular dosing of rabbits up to approximately 105 times the recommended ocular human dose, dogs up to approximately 18 times the recommended ocular human dose, and monkeys up to approximately 35 times the recommended ocular human dose. A long-term study was conducted with Brimonidine-Purite(tm) 0.1% or 0.2% administered to New Zealand White rabbits as 1 drop in 1 eye 3 times daily for 6 months. Both formulations were well tolerated. Slight, short term, dose-related sedation and hyperglycemia (up to 2.2-fold) were observed. These effects were considered exaggerated pharmacologic effects of alpha-2- adrenergic receptor activation. Plasma Cmax and AUC0-24 hr values were increased 20 and 6 times, respectively, the similar values estimated in humans treated with 1 drop of brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in both eyes three times per day.

Carcinogenicity

No compound-related carcinogenic effects were observed in either mice or rats following a 21- month and 24-month study, respectively. Dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved 106 and 145 times, respectively, the plasma drug concentration estimated in humans treated with one drop brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) into both eyes three times per day.

Mutagenicity

Brimonidine was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, host-mediated assay, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, cytogenic studies in mice and dominant lethal assay.

Reproduction and Teratology

No impairment of fertility and reproduction occurred in male rats when treated for 70 days prior to mating and female rats when treated for 14 days prior to mating and continuing through gestation and lactation with oral doses of brimonidine tartrate. Although blood drug levels were not determined in this study, it is estimated that the highest dose of brimonidine tartrate (0.66 mg/kg/day), achieved AUC values 60 times those seen in humans treated with 1 drop brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) in both eyes three times per day. Teratogenicity studies have been performed in rats and rabbits. 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 (1.65 mg/kg/day) and rabbits (3.33 mg/kg/day) achieved AUC values 258 and 17-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) 1 drop in both eyes three times per day. After oral dosing of 14C-brimonidine in pregnant rats, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent, producing 14C brimonidine concentrations in fetal blood that were 10-27% of that in maternal blood. Brimonidine was predominant in the placenta, uterus, and fetal liver but not in the maternal liver. The reproductive capabilities (survival, development, and behavior), of F1 and F2 generation rats were not affected when brimonidine tartrate was administered orally to F0 generation rats from gestation, day 16, through lactation, day 20. Although blood drug levels were not determined in this study, the high dose of brimonidine tartrate (0.66 mg/kg/day) was estimated to achieve AUC values that were 60-fold higher than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.15% (with Purite(r)) 1 drop in both eyes three times per day. There were no treatment-related reproductive and teratological effects observed in the F1 rat pup group, although a reduction in body weight was observed at a dose level of 1.65 mg base/kg/day, after 14 days. Dose related reduction in body weight gains were observed in rat dams at dose levels of 0.66 and 1.65 mg base/kg/day after 15 days. In one rabbit study, body weight gain and food consumption in the low and mid-dose groups was comparable to the control group throughout the study. Spontaneous abortions occurred in two of eight rabbits at the 3.3 mg base/kg/day level (gestation day 21 or 23), and may have been the result of the exaggerated pharmacological effects observed at this level. No abortions occurred at the 0.165 or 0.66 mg base/kg/day level. Maternal necropsy was generally unremarkable. There was no evidence of treatment-related embryotoxicity, fetal toxicity, or teratogenicity at dosage levels up to 3.3 mg base/kg/day (approximately 980 times the recommended human ocular dose). In another study involving 20 rabbit dams, dosed orally up to 2.64mg base/kg/day, no adverse effects were observed other than a decrease in weight gain during the dosing period, and no treatment related embryolethal or teratogenic effects were observed.

REFERENCES

study. Invest Ophthalmol Vis Sci 1993; 34(4): 929 (1138). Pasquale LR, Nordlund JR, Robin AL, Rudikoff MT, Ordman J, Walt JG, Chen KS. A comparison of the cardiovascular and pulmonary effects of brimonidine 0.2%, timolol 0.5% and betaxolol suspension 0.25%. Invest Ophthalmol Vis Sci 1993; 34(4): 929 (1139). Spaeth GL, David R, Clevenger CE, Perell HF, Siegel LI. The effects of brimonidine tartrate on the incidence of intraocular pressure (IOP) spikes following argon laser trabeculoplasty. Invest Ophthalmol Vis Sci 1992; 33(4): 1159 (2340). Toris CB, Camras CB, Yablonski ME. Effects of brimonidine on aqueous humour dynamics in human eyes. Invest Ophthalmol Vis Sci 1994; 35(4): 2052 (3703). Walters TR, Repass RL, Sargent JP, et al. A pilot study of the efficacy and safety of AGN 190342-LF 0.02% and 0.08% in patients with elevated intraocular pressure. Invest Ophthalmol Vis Sci 1991; 32(4): 988 (1572). Lai RK, Hasson D, Chun T, Wheeler L. Neuroprotective effect of ocular hypotensive agent brimonidine. XIth Congress of the European Society of Ophthalmology, 439-444, 1997. Product Monograph. Alphagan(r) P (Brimonidine Tartrate) Ophthalmic Solution, 0.15%. Allergan Inc, Date of Revision: October 30, 2003.

Table 1: Receptor Pharmacology of Brimonidine, Clonidine and p -Aminoclonidine
Radiogland Binding; Ki (nM) *			Functional EC 5 0 (nM) *
Compound	Alpha-1 a	Alpha-2 b	Alpha-1 c	Alpha-2 d
Brimonidine	1850 +- 322 (5)	1.9 +- 0.5 (6)	1490 +- 214 (12)	1.0 +- 0.1 (24)
Clonidine	513 +- 108 (4)	3.4 +- 0.4 (6)	293 +- 47 (4)	4.4 +- 0.4 (11)
p -Aminoclonidine	181 +- 18 (4)	7.8 +- 1.2 (2)	180 +- 10 (8)	1.9 +- 0.2 (9)

Table 2: The IOP Response to Chronic Administration of Brimonidine (BID for 6 months) in Rabbits
Concentration (%) a	Acute	Three Months	Six Months
0.08	4.3 b *	5.1 *	3.8 *
0.2	4.0 *	6.0 *	5.1 *
0.5	0.2	6.0 *	6.9 *
0.8	1.0	6.5 *	7.1 *

Table 3: Effects of Brimonidine on Aqueous Humour Dynamics
	Control Eye		Treated Eye
	Baseline	Day 8	Baseline	Day 8
lOP	21.3 +- 1.0	20.0 +- 0.6 *	20.6 +- 0.8	15.9 +- 0.6 * +
Fa	2.6 +- 0.2	2.3 +- 0.1 *	2.5 +- 0.2	2.0 +- 0.1 *
Fu fl	0.35 +- 0.20	0.50 +- 0.17	0.12 +- 0.28	0.65 +- 0.16 *
F u ton	0.28 +- 0.31	0.08 +- 0.35	0.25 +- 0.37	1.02 +- 0.11 * +
C fl	0.22 +- 0.03	0.16 +- 0.02 *	0.22 +- 0.03	0.21 +- 0.03
C ton	0.17 +- 0.01	0.19 +- 0.02	0.19 +- 0.03	0.16 +- 0.02
Pev	8.9 +- 0.5	8.5 +- 04	8.8 +- 0.5	9.2 +- 0.3

Species	Route	LD 5 0 (mg/kg) *	MLD (mg/kg)
Mouse	oral	50	>8 * *
Mouse	i.v *	50	Not performed
Rat	oral	100	>8 * *
Rat	i.v.	100-150	Not performed
Rabbit	oral	Not performed	>6
Rabbit	i.v.	Not performed	20-50
Dog	oral	Not performed	0.5
Dog	i.v.	Not performed	0.05

PRODUCT MONOGRAPH

APO-BRIMONIDINE P

Brimonidine Tartrate Ophthalmic Solution, 0.15% Sterile

Relatively selective a2-adrenoceptor Agonist Elevated Intraocular Pressure Therapy

APOTEX INC.

Signet Drive

Weston, Ontario DATE OF REVISION:

M9L 1T9 October 31, 2007

Control No. 110427