Timolol Maleate-Ex Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4

1 INDICATIONS ............................................................................................................... 4

1.1 Pediatrics .................................................................................................................... 4

1.2 Geriatrics .................................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ................................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ........................................................... 5

4.4 Administration ............................................................................................................ 6

4.5 Missed Dose ............................................................................................................... 6

5 OVERDOSAGE .............................................................................................................. 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 7

7 WARNINGS AND PRECAUTIONS .................................................................................. 8

7.1 Special Populations .................................................................................................. 10

7.1.1 Pregnant Women ........................................................................................... 10

7.1.2 Breast-feeding ................................................................................................ 10

7.1.3 Pediatrics ........................................................................................................ 10

7.1.4 Geriatrics ........................................................................................................ 10

8 ADVERSE REACTIONS ................................................................................................ 10

8.1 Adverse Reaction Overview ...................................................................................... 10

8.2 Clinical Trial Adverse Reactions ................................................................................ 11

8.3 Less Common Clinical Trial Adverse Reactions ......................................................... 11

8.5 Post-Market Adverse Reactions ............................................................................... 12

9 DRUG INTERACTIONS ......................................................................................................... 12

9.2 Drug Interactions Overview ...................................................................................... 12

9.3 Drug-Behavioural Interactions .................................................................................. 13

9.4 Drug-Drug Interactions ............................................................................................. 13

9.5 Drug-Food Interactions ............................................................................................ 13

9.6 Drug-Herb Interactions ............................................................................................. 13

9.7 Drug-Laboratory Test Interactions ........................................................................... 13

10 CLINICAL PHARMACOLOGY ....................................................................................... 13

10.1 Mechanism of Action .............................................................................................. 13

10.2 Pharmacodynamics ................................................................................................ 14

10.3 Pharmacokinetics ................................................................................................... 14

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 14

PART II: SCIENTIFIC INFORMATION ....................................................................................... 15

13 PHARMACEUTICAL INFORMATION ............................................................................ 15

14 CLINICAL TRIALS ........................................................................................................ 15

15 MICROBIOLOGY ........................................................................................................ 15

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 15

PATIENT MEDICATION INFORMATION .................................................................................. 19

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

T-LO is indicated for the reduction of elevated intraocular pressure (IOP) in adult patients with:

• Chronic open glaucoma.
• Ocular hypertension.
• Aphakic patients with glaucoma, including those wearing contact lenses.
• Narrow angles and a history of spontaneous or iatrogenically-induced narrow-angle closure in the opposite eye in whom reduction of IOP is necessary (see 7 WARNINGS AND PRECAUTIONS, ophthalmologic).

TIMOLOL MALEATE-EX is indicated for the reduction of IOP in adult patients with:

• Chronic open-angle glaucoma.
• Ocular hypertension.

1.1 Pediatrics

T-LO and TIMOLOL MALEATE-EX are not recommended for use in children or adolescents. The safety and effectiveness of T-LO and TIMOLOL MALEATE-EX in pediatric patients < 18 years of age have not been established.

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

T-LO and TIMOLOL MALEATE-EX are contraindicated in patients with:

• Hypersensitivity to timolol or any ingredient in the formulation or component of the container (see 6 Dosage forms, Strengths, Composition and Packaging).
• Hypersensitivity to other beta-blockers.
• Bronchospasm, including bronchial asthma, a history of bronchial asthma, or chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, second and third degree atrioventricular block, overt cardiac failure, or cardiogenic shock.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

T-LO

When a patient is transferred from another topical ophthalmic beta-adrenergic blocking agent, that agent should be discontinued after proper dosing on one day and treatment with T-LO started on the following day with 1 drop of 0.25% T-LO in the affected eye(s) twice a day. The dose may be increased to 1 drop of 0.5% T-LO twice a day if the clinical response is not adequate.

When a patient is transferred from a single anti-glaucoma agent, other than a topical ophthalmic beta-adrenergic blocking agent, continue the agent already being used and add one drop of 0.25% T-LO in each affected eye(s) twice a day. On the following day, discontinue the previously used anti-glaucoma agent completely and continue with T-LO. If a higher dosage of T-LO is required, substitute one drop of 0.5% solution in each affected eye(s) twice a day.

When a patient is transferred from several concomitantly administered anti-glaucoma agents, individualization is required. The physician may be able to discontinue some or all of the other anti-glaucoma agents. Adjustments should involve one agent at a time.

TIMOLOL MALEATE-EX

When a patient is transferred from T-LO to TIMOLOL MALEATE-EX, the solution should be discontinued after proper dosing on one day, and treatment with the same concentration of TIMOLOL MALEATE-EX started on the following day.

When a patient is transferred from another topical ophthalmic beta-adrenergic blocking agent, that agent should be discontinued after proper dosing on one day and treatment with TIMOLOL MALEATE-EX started on the following day with 1 drop of 0.25% TIMOLOL MALEATE-EX in the affected eye(s) once a day. The dose may be increased to 1 drop of 0.5% TIMOLOL MALEATE-EX once a day if the clinical response is not adequate.

When a patient is transferred from a single anti-glaucoma agent, other than a topical ophthalmic beta-adrenergic blocking agent, continue the agent already being used and add one drop of 0.25% TIMOLOL MALEATE-EX in each affected eye(s) once a day. On the following day, discontinue the previously used anti-glaucoma agent completely and continue with TIMOLOL MALEATE-EX. If a higher dosage of TIMOLOL MALEATE-EX is required, substitute one drop of 0.5% solution in each affected eye(s) once a day.

4.2 Recommended Dose and Dosage Adjustment

T-LO

The recommended starting dosage is one drop of 0.25% solution in the affected eye(s) twice a day.

If clinical response is not adequate, the dosage may be changed to one drop of 0.5% solution in each affected eye(s) twice a day. If the patient’s IOP is still not at a satisfactory level on this regimen, concomitant therapy with miotics, epinephrine and systemically administered carbonic anhydrase inhibitors may be instituted with T-LO. Other topically applied medications should be administered at interval of not less than 10 minutes.

Since in some patients the IOP-lowering response to T-LO Solution may require a few weeks to stabilize, evaluation should include a determination of IOP after approximately 4 weeks of treatment with T-LO.

If IOP is maintained at satisfactory levels, the dosage schedule may be changed to one drop a day in the affected eye(s). Because of naturally occurring diurnal variations in IOP, satisfactory response to the once-a-day dose is best determined by measuring IOP at different times during the day.

TIMOLOL MALEATE-EX

The usual starting dose is one drop of 0.25% in the affected eye(s) once a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5% in the affected eye(s) once a day.

If the patient’s IOP is still not at a satisfactory level on this regimen, concomitant therapy with miotics, epinephrine and systemically administered carbonic anhydrase inhibitors may be instituted with TIMOLOL MALEATE-EX. Other topically applied medications should be administered at intervals of not less than 10 minutes. Health Canada has not authorized an indication for pediatric use.

4.4 Administration

Nasolacrimal occlusion or gently closing the eyelid for 2 minutes after instillation (of either T-LO or TIMOLOL MALEATE-EX) is recommended. This may reduce the systemic absorption of medications administered via the ocular route and result in a decrease in systemic adverse events.

To avoid contamination, patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. The contents should not be used for more than one month after the date on which the container is first opened.

If using another eye medication, use it at least 10 minutes before or after the use of T-LO or TIMOLOL MALEATE-EX.

4.5 Missed Dose

Patients who miss a dose, should be advised to apply it as soon as possible. However, if it is almost time for the next dose, patients are advised to skip the missed dose and go back to regular dosing schedule to avoid doubling the dose.

5 OVERDOSAGE

No data are available in regard to overdosage in humans.

The most common signs and symptoms to be expected with overdosage with administration of a systemic beta-adrenergic receptor blocking agent are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure.

The following therapeutic measures should be considered:

1. 1) Gastric lavage: if ingested.
2. 2)

   Symptomatic bradycardia: use atropine sulfate intravenously in a dosage of 0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker

   1. may be considered.
3. 3) Hypotension: use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or levarterenol. In refractory cases the use of glucagon hydrochloride has been reported to be useful.
4. 4) Bronchospasm: use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered.
5. 5) Acute cardiac failure: conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases the use of intravenous aminophylline is suggested. This may be followed if necessary by glucagon hydrochloride which has been reported to be useful.
6. 6) Heart block (second or third degree): use isoproterenol hydrochloride or a transvenous cardiac pacemaker.]

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

T-LO is a sterile, clear, isotonic, buffered, colourless to pale yellow aqueous solution. T-LO, 0.5%, is supplied in 5 mL and 10 mL white, opaque, plastic ophthalmic DROP-TAINER* dispensers with a

controlled drop tip, and the 0.25% is supplied in 10 mL.

TIMOLOL MALEATE-EX is a sterile, isotonic buffered, colourless to pale yellow, clear to slightly translucent, and slightly viscous aqueous solution. TIMOLOL MALEATE-EX, 0.25% or 0.5%, is supplied in 5 mL white, opaque, plastic ophthalmic DROP-TAINER* dispensers with a controlled drop tip.

7 WARNINGS AND PRECAUTIONS

General

FOR TOPICAL OPHTHALMIC USE ONLY.

T-LO and TIMOLOL MALEATE-EX contain timolol, a beta-adrenergic blocking agent. As with other topically applied ophthalmic agents, timolol may be absorbed systemically. The same types of cardiovascular, pulmonary and other adverse reactions reported with systemic beta-adrenergic blocking agents may occur with topical ophthalmic administration.

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or in diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia. They may also mask the signs of hyperthyroidism.

Beta-adrenergic blocking agents have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms, such as diplopia, ptosis and generalized weakness.

The effect on IOP or the known effects of systemic beta-blockade may be potentiated when T-LO or TIMOLOL MALEATE-EX is given to patients already receiving an oral beta-adrenergic blocking agent. The response of these patients should be closely observed. The use of two local beta-adrenergic blocking agents is not recommended.

Cardiovascular

Cardiac reactions, and rarely, death in association with cardiac failure, have been reported following administration of timolol maleate.

T-Lo and TIMOLOL MALEATE-EX are not recommended for use in patients with cardiovascular diseases (e.g., coronary heart disease, Prinzmetal’s angina, and cardiac failure) and hypotension, as it can cause worsening of Prinzmetal’s angina, severe peripheral and central nervous system disorders, and hypotension. Therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and for adverse reactions.

Caution is advised when using T-LO or TIMOLOL MALEATE-EX in patients with severe peripheral circulatory disturbances/disorders, such as severe forms of Raynaud’s disease or Raynaud’s syndrome.

Drug Interactions

Mydriasis resulting from concomitant use of ophthalmic beta-blockers, such as timolol, and adrenaline (epinephrine) has been reported occasionally.

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic solutions with beta-blockers, such as timolol, are administered concomitantly with oral calcium channel blockers, quinidine, catecholamine-depleting drugs, beta-adrenergic blocking agents, antiarrhythmics (e.g. amiodarone, digitalis glycosides or parasympathomimetics).

Potentiated systemic beta-blockade (e.g. decreased heart rage) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, cimetidine, fluoxetine, paroxetine) and timolol.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-adrenergic blocking agents.

Driving and Operating Machinery

T-LO and TIMOLOL MALEATE-EX may cause temporary blurred vision or other visual disturbances that can affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

Immune

Anaphylactic Reactions: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge to such allergens, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions. In such cases, alternatives to epinephrine should be considered.

Ophthalmologic

In patients with angle-closure glaucoma, the immediate objective of treatment is to re-open the angle. This requires constricting the pupil with a miotic. T-LO and TIMOLOL MALEATE-EX have little or no effect on the pupil. When T-LO or TIMOLOL MALEATE-EX is used to reduce elevated intraocular pressure in angle-closure glaucoma, they should be used with a miotic and not alone.

As with the use of other anti-glaucoma drugs, diminished responsiveness to T-LO after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least three years, no significant difference in mean IOP has been observed after initial stabilization. In a long-term clinical trial of 157 patients, TIMOLOL MALEATE-EX 0.5% once daily maintained IOP reductions over the one year study period.

T-LO contains the preservative benzalkonium chloride, which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses is to be avoided. Patients must be instructed to remove contact lenses prior to instillation of T-LO and wait at least 15 minutes after dosing before re-inserting contact lenses.

Benzalkonium chloride has also been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Close monitoring is required with frequent or prolonged use.

TIMOLOL MALEATE-EX contains the preservative, benzododecinium bromide, which is a quaternary ammonium compound that may be absorbed by soft contact lenses. Studies have not been performed with TIMOLOL MALEATE-EX in patients wearing contact lenses. Patients should be instructed to consult with their physician prior to use.

Choroidal detachment has been reported with administration of aqueous suppression therapy (e.g., timolol, acetazolamide) after filtration procedures.

Peri-Operative Considerations

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects, such as that of adrenaline. The anesthesiologist should be informed if and when patients are receiving timolol.

Reproductive Health: Female and Male Potential

• Function

Sexual Function/Reproduction: There are no data on the effect of timolol on human fertility.

Respiratory

Respiratory reactions, including death due to bronchospasm in patients with asthma, have been reported following administration of timolol maleate.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Epidemiological studies have not revealed malformative effects, but show a risk of intrauterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g., bradycardia, hypotension, respiratory distress and hypoglycemia) have been observed in the neonate when beta-blockers have been administered until delivery. T-LO and TIMOLOL MALEATE-EX should not be used during pregnancy unless clearly necessary. If T-LO or TIMOLOL-MALEATE-EX is administered until delivery, the neonate should be carefully monitored during the first days of life.

7.1.2 Breast-feeding

T-LO and TIMOLOL MALEATE-EX should not be used by nursing women. Beta-blockers are excreted in breast milk, having the potential to cause serious undesirable effects in the breastfeeding infant.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

In clinical studies with T-LO, the most common ocular adverse reactions reported were ocular hyperemia (5.1%) and eye irritation (2.4%). Other ocular adverse reactions occurring with a frequency of at least 1% were eye pain, ocular discomfort, and vision blurred.

In clinical studies with TIMOLOL MALEATE-EX, the most common ocular adverse events were blurred vision (4.1%) and discomfort (2.9%). Other ocular adverse events occurring with a frequency of at least 1% were: blepharitis, hyperemia, pruritus, foreign body sensation, lid margin crusting and tearing.

T-LO and TIMOLOL MALEATE-EX are usually well tolerated.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, 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 reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Table 2- Treatment-Related Adverse Reactions

8.3 Less Common Clinical Trial Adverse Reactions

Less Common Clinical Trial Adverse Drug Reactions with T-Lo (<1%):

Cardiac disorders: bradycardia, myocardial infarction

Eye disorders: corneal erosion, punctate keratitis, keratitis, iritis, conjunctivitis, blepharitis, reduced visual acuity (including ptosis and refractive changes due to withdrawal of miotic therapy in some cases), photophobia, dry eye, lacrimation increased, eye discharge, eye pruritus, eyelid margin crusting, anterior chamber inflammation, eyelid edema, conjunctival hyperemia, uveitis, diplopia, asthenopia, eczema of eyelids, erythema of eyelid, eyelid pruritus, conjunctival edema, corneal pigmentation

Gastrointestinal disorders: dysgeusia, dyspepsia, abdominal discomfort, dry mouth

General disorders and administration site conditions: fatigue, asthenia, chest discomfort

Nervous system disorders: headache, cerebral ischemia, dizziness, migraine

Psychiatric disorders: depression

Respiratory, thoracic and mediastinal disorders: asthma, bronchitis, dyspnea, chronic obstructive pulmonary disease, bronchospasm, cough, wheezing, nasal congestion

Skin and subcutaneous tissue disorders: swelling face, erythema

Vascular disorders: hypotension, blood pressure increased, edema peripheral, peripheral coldness

Causal Relationship Unknown:

The following adverse reactions have been reported but a causal relationship to therapy with T-LO has not been established: anorexia, aphakic cystoid, CNS effects (e.g., anxiety, confusion, disorientation, hallucinations, nervousness, somnolence and other psychic disturbances), dry mouth, dyspepsia, hypertension, macular edema, nasal congestion, and retroperitoneal fibrosis.

The adverse reactions listed for T-LO are potential adverse reactions for TIMOLOL MALEATE-EX.

Adverse reactions reported in clinical experience with oral timolol may be considered potential side effects of ophthalmic timolol.

8.5 Post-Market Adverse Reactions

• choroidal detachment (following filtration surgery), eyelid ptosis.
• cardiac arrest, atrioventricular block (complete, lower degree or aggravation), arrhythmia, palpitations.
• vomiting, diarrhea, nausea.
• angioedema, hypersensitivity.
• hypoglycemia.
• arthropathy.
• cerebrovascular accident, syncope, paresthesia.
• insomnia, amnesia, nightmares.
• sexual dysfunction.
• urticaria, psoriasis, rash, alopecia.

Vascular disorders: Raynaud’s phenomenon.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

The following may interact with T-LO or TIMOLOL MALEATE-EX:

• Adrenaline (epinephrine) (used to treat life-threatening allergic reactions).
• A group of medicines called oral calcium channel blockers such as diltiazem, verapamil.
• A group of medicines called Catecholamine-depleting drugs (e.g. reserpine).
• Beta-adrenergic blocking agents commonly referred to as beta-blockers such as atenolol, labetalol, metoprolol, nadolol, propranolol, sotalol.
• Medications used to treat certain type of abnormal heart rhythm such as amiodarone, digoxin, quinidine.
• Clonidine (a medication used to treat high blood pressure). Do not stop taking clonidine without talking to healthcare professional.

• Cimetidine (a medication used to treat stomach problem), Fluoxetine and paroxetine [both

  • ]

9.3 Drug-Behavioural Interactions

Not available at the time of initial authorization.

9.4 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Timolol maleate is a general beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant or local anesthetic (membrane-stabilizing) activity.

T-LO and TIMOLOL MALEATE-EX, when applied topically in the eye, has the action of reducing elevated as well as normal IOP, whether or not associated with glaucoma. Elevated IOP is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.

The onset of reduction in IOP following administration of T-LO can usually be detected within 30 minutes after a single dose. The maximum effect usually occurs in one to two hours. Significant lowering of IOP has been maintained for periods as long as 24 hours with 0.25% or 0.5% T-LO twice a day and 0.25% or 0.5% TIMOLOL MALEATE-EX once per day. Repeated observations indicate that the IOP-lowering effect of T-LO and TIMOLOL MALEATE-EX is well maintained over study periods of three years and one year, respectively.

The precise mechanism of the ocular hypotensive action of T-LO is not clearly established at this time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. Unlike miotics, T-LO and TIMOLOL MALEATE-EX reduces IOP with little or no effect on accommodation or pupil size. These changes in visual acuity due to increased accommodation are uncommon, and dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts the inability to see around lenticular opacities when the pupil is constricted by miotics is avoided.

10.2 Pharmacodynamics

In clinical studies, T-LO and TIMOLOL MALEATE-EX were generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine.

As with the use of other anti-glaucoma drugs, diminished responsiveness to T-LO after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least three years, no significant difference in mean IOP has been observed after initial stabilization. In a long-term clinical trial of 157 patients, TIMOLOL MALEATE-EX 0.5% once daily maintained IOP reductions over the one year study period.

T-LO has also been used in patients with glaucoma wearing conventional (polymethylmethacrylate) hard contact lenses, and has generally been well tolerated. T-LO has not been studied in patients wearing lenses made with materials other than polymethylmethacrylate.

In controlled, double-masked, multicenter clinical studies, TIMOLOL MALEATE-EX administered once daily was shown to be equally effective in lowering IOP as the equivalent concentration of TIMOPTIC® (timolol maleate solution) administered twice daily and TIMOPTIC-XE® once daily. The effect of timolol in lowering IOP was evident for 24 hours with a single dose of TIMOLOL MALEATE-EX. Repeated observations over a twelve month study period indicate that the IOP-lowering effect of TIMOLOL MALEATE-EX was consistent.

TIMOLOL MALEATE-EX administered once daily had a safety profile similar to that of an equivalent concentration of TIMOPTIC® administered twice daily and TIMOPTIC-XE® once daily. Due to the physical characteristics of the formulation, transient blurred vision was reported in patients administered TIMOLOL MALEATE-EX.

TIMOLOL MALEATE-EX has not been studied in patients wearing contact lenses.

Unlike miotics, T-LO and TIMOLOL MALEATE-EX reduce IOP with little or no effect on accommodation or pupil size.

10.3 Pharmacokinetics

Not available at the time of initial authorization.

11 STORAGE, STABILITY AND DISPOSAL

Protect from light. Keep out of the reach and sight of children.

T-LO: Store at room temperature (15º C - 30º C).

TIMOLOL MALEATE-EX: Store at 4º C - 30º C.

The contents of T-LO and TIMOLOL MALEATE-EX should not be used for more than one month after the date on which the container is first opened.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Timolol Maleate

Chemical name: (-)-1-(tert-butyl amino)-3-[(4-morpholino)-1,2,5-thiadiazol-3-yl)-oxy]-2-propanol maleate (1:1) salt

Molecular formula and molecular mass: C₁₃H₂₄N₄O₃S∙C₄H₄O₄, 432.49

Structural formula:

Physicochemical properties:

Melting Point: 201.5 - 202.5ºC

pKa: 9.2

pH: approximately 4 in a 2% aqueous solution

Physical Description: White, odourless, crystalline powder which is soluble in water, methanol, and alcohol.

14 CLINICAL TRIALS

Not available at the time of initial authorization.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Ocular Effects

No adverse ocular effects were observed in rabbits and dogs administered Timolol Maleate Ophthalmic Solution topically in studies lasting one and two years respectively.

Acute Toxicity (LD₅₀)

Signs of toxicity occurred immediately after intravenous administration and from 10 to 30 minutes following oral, intraperitoneal or subcutaneous administration. The signs observed included lacrimation, ataxia, tremors and bradypnea. Clonic convulsions usually preceded death.

Oral Interaction Studies

Oral acute interaction studies in mice in which timolol maleate was administered with probenecid, methyldopa, hydralazine, hydrochlorothiazide, or tolbutamide, showed that these drugs had no effect on the toxicity of timolol maleate. Timolol maleate had no effect on hypoprothrombinemia induced by bishydroxycoumarin in the dog.

Subacute Toxicity

In rats treated with 100 to 400 mg/kg for seven weeks, excessive salivation seen 5 to 10 minutes after dosing has a dose related incidence in the first week of the study. At necropsy, organ weight studies revealed a significant increase in the kidneys, spleen and liver of some treated animals. Except for splenic congestion, there were no morphological changes to account for the increase in organ weights. Rats treated with 1 gram per day for eight weeks exhibited ptylamism, muscle tremors and transient pale extremities.

In dogs, doses of 200 mg/kg or higher, were lethal to some animals. Low grade tubular nephrosis and trace amounts of hyaline casts in the collecting and convoluted tubules occurred in one of two dogs administered 100 mg/kg/day and in both dogs receiving 400 mg/kg/day. Small foci of tubular degeneration and regeneration occurred in the nephrotic areas. Similar slight multi focal degeneration of the collecting tubules in the medulla of both kidneys was evident in one of four dogs in a 15-day intravenous toxicity study.

Chronic Toxicity

Rats: Timolol was administered orally to rats at dose levels 5, 10 and 25 mg/kg/day for up to 67 weeks. No physical signs, ocular signs or deaths which could be attributed to the drug were evident.

Dogs: In a 54 week oral study, timolol was administered at doses of 5, 10 and 25 mg/kg/day. Body weight and food consumption were normal and no physical signs attributable to treatment were evident. Slight focal hyperplasia of the transitional epithelium was seen in the renal pelvis of one dog receiving 25 mg/kg/day.

Carcinogenicity: Lifetime studies with timolol have been completed in rats at oral doses of 25, 100 and 300 mg/kg/day and in mice at oral doses of 5, 50 and 500 mg/kg/day. In male and female rats and in male mice at all dose levels, and in female mice at dose levels of 5 and 50 mg/kg/day, timolol demonstrated no carcinogenic effect. There was a slight increase in the incidence of mammary adenocarcinomas in female mice that received 500 mg/kg/day (about 500 times the maximum recommended human oral dose, on a mg/kg/day basis). Timolol caused dose-related elevations of serum prolactin in female mice at doses of 100 mg/kg or more, but only very slight transient elevations were found in male mice at does of 500 mg/kg. Since numerous studies have demonstrated that drugs which cause elevations if serum prolactin are associated with mammary tumours in rodents, the mammary tumours in the female mice in the highest dosage group of this study were considered to have resulted from an increased serum prolactin. In humans, no such association between serum prolactin and mammary carcinoma has been established. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

Mutagenicity: Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse and the Micronucleus test and Ctyogenic assay (dose up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 µg/mL). In Ames tests, the high test concentrations of timolol employed, 5 000 or 10 000 µg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays) but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose response relationship was observed, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion of a positive Ames Test.

Reproductive and Teratology: Teratogenic studies in the mouse and rabbit at dose levels of 2 to 50 mg/kg/day did not reveal evidence of teratogenicity but did suggest embryotoxicity at the highest dose. Oral administration of timolol maleate to rats at dose levels of 4 to 100 mg/kg/day did not adversely affect the fertility of male or female rats, their reproductive performance, or the development of their offspring.

TIMOLOL MALEATE-EX contains xanthan gum at concentrations up to 0.6%. The oral LD50 value for xanthan gum is greater than 5 g/kg in rats. Xanthan gum was not classified as an ocular irritant when a single 0.2 mL dose of a 1% xanthan gum solution was administered to rabbit eyes. Xanthan gum did not elicit any dermal responses when a skin sensitization assay was conducted in guinea pigs. In addition, oral administration (in feed) of up to 1 g/kg/day of xanthan gum for two years to rats and dogs did not elicit any treatment-related changes in hematology parameters or histopathology. Likewise, no deaths were observed in either study.

In rabbits treated twice daily for three months with topical ocular administration of TIMOLOL MALEATE-EX 0.5%, ocular effects were minimal in nature, confined to the conjunctiva, comparable to the ocular findings observed in the vehicle control group and the TIMOPTIC-XE® group, and judged to be of no clinical significance.

Results from a one year study of primates treated twice daily with topical ocular administration of TIMOLOL MALEATE-EX 0.5% demonstrated that there were no treatment-related findings with regard to clinical signs, body weight difference, biomicroscopic observations of eyes, indirect ophthalmoscopic evaluations, pachymetry measurements, specular microscopy and clinical pathology.