MYLAN-TIMOLOL SOLUTION

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Active ingredient:
TIMOLOL (TIMOLOL MALEATE)
Available from:
MYLAN PHARMACEUTICALS ULC
ATC code:
S01ED01
INN (International Name):
TIMOLOL
Dosage:
0.25%
Pharmaceutical form:
SOLUTION
Composition:
TIMOLOL (TIMOLOL MALEATE) 0.25%
Administration route:
OPHTHALMIC
Units in package:
5ML/10ML
Prescription type:
Prescription
Therapeutic area:
BETA-ADRENERGIC AGENTS
Product summary:
Active ingredient group (AIG) number: 0131275001; AHFS: 52:40.08
Authorization status:
APPROVED
Authorization number:
00893773
Authorization date:
2009-07-21

Documents

PRODUCT MONOGRAPH

Pr

Mylan-Timolol

(Timolol Maleate Ophthalmic Solution)

Ophthalmic Solution 0.25% and 0.5%

Elevated Intraocular Pressure Therapy

Mylan Pharmaceuticals ULC

Date of Revision

85 Advance Road

July 20, 2010

Etobicoke, Ontario

M8Z 2S6

Control # 137993

2

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION

………………………………3

SUMMARY PRODUCT INFORMATION………………………………………………... 3

INDICATIONS AND CLINICAL USE……………………………………………………. 3

CONTRAINDICATIONS………………………………………………………………. 3

WARNINGS AND PRECAUTIONS……………………………………………………. 4

ADVERSE REACTIONS……………………………………………………………….. 6

DRUG INTERACTIONS……………………………………………………………….. 8

DOSAGE AND ADMINISTRATION……………………………………………………. 9

OVERDOSAGE………………………………………………………………………. 10

ACTION AND CLINICAL PHARMACOLOGY…………………………………………. 10

STORAGE AND STABILITY………………………………………………………….. 11

DOSAGE FORMS, COMPOSITION AND PACKAGING………………………………. 11

PART II: SCIENTIFIC INFORMATION

……………………………………………

PHARMACEUTICAL INFORMATION………………………………………………….. 13

CLINICAL TRIALS…………………………………………………………………….. 13

DETAILED PHARMACOLOGY………………………………………………………. 14

TOXICOLOGY……………………………………………………………………….. 14

BIBLIOGRAPHY……………………………………………………………………… 17

PART III: CONSUMER INFORMATION

…………………………………………….. 19

3

Pr

Mylan-Timolol

Timolol Maleate Ophthalmic Solution, USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal Ingredients

Ophthalmic

Ophthalmic Solution

0.25% and 0.5%

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

Mylan-Timolol

(timolol maleate ophthalmic solution, USP) is indicated for the reduction of elevated

intraocular pressure.

In clinical trials

timolol maleate

has been shown to reduce intraocular pressure in:

Patients with chronic open-angle glaucoma

Patients with ocular hypertension

Aphakic patients having glaucoma, including those wearing contact lenses

Patients with narrow angles and a history of spontaneous or iatrogenically-induced narrow-

angle closure in the opposite eye in whom reduction of intraocular pressure is necessary (see

WARNINGS AND PRECAUTIONS).

CONTRAINDICATIONS

Hypersensitivity to any component of this product. For a complete listing of components see

the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product

monograph.

Bronchospasm, including bronchial asthma or a history of bronchial asthma or chronic

obstructive pulmonary disease.

Sinus bradycardia; second-and third-degree atrioventricular block; overt cardiac failure;

cardiogenic shock.

4

WARNINGS AND PRECAUTIONS

General

As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The

same adverse reactions reported with systemic beta-adrenergic blocking agents may occur with

topical administration.

Timolol maleate

should be used 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.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the

angle. This requires constricting the pupil with a miotic. Timolol maleate has little or no effect

on the pupil. When

timolol maleate

is used to reduce elevated intraocular pressure in angle-closure

glaucoma they should be used with a miotic and not alone.

Cardiac failure should be adequately controlled before beginning therapy with

timolol maleate.

patients with a history of severe cardiac disease, signs of cardiac failure should be watched for

and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with

asthma and rarely death in association with cardiac failure, have been reported following

administration of timolol maleate.

Because of the potential effects of beta-adrenergic blocking agents on blood pressure and pulse,

these agents should be used with caution in patient with cerebrovascular insufficiency. If signs

or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with

timolol maleate

, alternative therapy should be considered.

Endocrine and Metabolism

Thyrotoxicosis

-adrenergic blocking agents may mask certain clinical signs of hyperthyroidism (e.g.,

tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid

abrupt withdrawal of

-adrenergic blocking agents which might precipitate a thyroid storm.

Immune

Risk from Anaphylactic Reaction

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 with such allergens,

either accidental, diagnostic, or therapeutic. These patients may be more resistant to treatment of

5

anaphylactic reactions with the usual doses of epinephrine since timolol may blunt the beta

agonist effect of epinephrine. In such cases, alternatives to epinephrine should be considered.

Ophthalmologic

Choroidal Detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g.,

timolol, acetazolamide or combination) after filtration procedures. Management of eyes with

chronic or recurrent choroidal detachment should include stopping all forms of aqueous suppressant

therapy and treating endogenous inflammation vigorously.

As with the use of other antiglaucoma drugs, diminished responsiveness to

timolol maleate

after

prolonged therapy has been reported in some patients. However, in clinical studies in which 164

patients have been followed for at least 3 years, no significant difference in mean intra ocular

pressure has been observed after initial stabilization.

Contact Lenses

The preservative in

timolol maleate

is benzalkonium chloride. This preservative is a quaternary

ammonium compound that may be absorbed by soft contact lenses. Therefore,

timolol maleate

should not be administered while wearing soft contact lenses. The contact lenses should be

removed before application of the drops and not be reinserted earlier than 15 minutes after use.

Neurologic

Muscle Weakness

-adrenergic blockade has been reported to increase muscle weakness consistent with certain

myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been

reported rarely to increase muscle weakness in some patients with myasthenic symptoms.

Peri-Operative Considerations

Major Surgery

The necessity or desirability of withdrawal of

-adrenergic blocking agents prior to major

surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to

respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general

anesthesia in surgical procedures. Some patients receiving beta-adrenergic blocking agents have

experienced protracted severe hypotension during anesthesia. Difficulty in restarting and

maintaining the heartbeat has also been reported. For these reasons, in patients undergoing

elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic blocking

agents. If necessary during surgery, the effects of

-adrenergic blocking agents may be reversed

by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.

6

Special Populations

Pregnant Women:

Timolol maleate

has not been studied in human pregnancy. The use of

timolol maleate

requires that

the anticipated benefit be weighed against possible hazards.

Nursing Women:

Timolol is detectable in human milk. Because of the potential for serious adverse reactions from

timolol 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

Safety and effectiveness in children have not been established.

ADVERSE REACTIONS

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

Timolol maleate

is usually well tolerated.

The following adverse reactions have been reported with ocular administration of this or other

timolol maleate formulations, either in clinical trials or since the drug has been marketed.

Body as a Whole

Headache, asthenia, fatigue, chest pain.

Cardiovascular

Aggravation or precipitation of certain cardiovascular pulmonary and other disorders presumably

related to effects of systemic beta blockade has been reported (see CONTRAINDICATIONS and

WARNINGS AND PRECAUTIONS). These include bradycardia, arrhythmia, hypotension,

syncope, heart block, cerebrovascular accident, cerebral ischemia, palpitation, cardiac arrest,

congestive heart failure, edema, claudication, Raynaud’s phenomenon, cold hands and feet and

in insulin-dependent diabetics masked symptoms of hypoglycemia have been reported rarely.

Digestive

Nausea, diarrhea, dyspepsia, dry mouth.

7

Hypersensitivity

Signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localized

and generalized rash.

Immunologic

Systemic lupus erythematosus.

Integumentary

Alopecia, psoriasiform rash or exacerbation of psoriasis.

Nervous System/Psychiatric

Dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of

myasthenia gravis, paresthesia.

Respiratory

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory

failure, dyspnea, cough.

Special Senses

Signs and symptoms of ocular irritation: including burning and stinging, conjunctivitis, blepharitis,

keratitis, decreased corneal sensitivity, and dry eyes.

Visual disturbances: including refractive changes (due to withdrawal of miotic therapy in some

cases), diplopia, ptosis, and choroidal detachment following filtration surgery (see WARNINGS

AND PRECAUTIONS).

Tinnitus.

Urogenital

Decreased libido, Peyronie’s disease.

Causal Relationship Unknown

The following adverse reactions have been reported but a causal relationship to therapy with

timolol

maleate

has not been established: aphakic cystoid macular edema, nasal congestion, anorexia, CNS

effects (e.g., behavioral changes including confusion, hallucinations, anxiety, disorientation,

nervousness, somnolence, and other psychic disturbances), hypertension, retroperitoneal fibrosis

and pseudopemphigoid.

Potential Adverse Reactions

Adverse reactions reported in clinical experience with systemic timolol maleate may be considered

potential side effects of ophthalmic timolol maleate.

8

DRUG INTERACTIONS

Drug-Drug Interactions

Beta-adrenergic Blockers

Patients who are already receiving a beta blocker systemically and who are given

timolol maleate

should be observed for a potential additive effect on the intraocular pressure or on the known

systemic effects of beta blockers (hypotension and/or bradycardia). The concomitant use of two

topical beta-adrenergic blocking agents is not recommended.

Calcium Channel Blockers or Catecholamine-depleting Drugs

The potential exists for additive effects and production of hypotension and/or marked

bradycardia when

timolol maleate

is administered together with an oral calcium channel blocker or

catecholamine-depleting drugs such as reserpine.

Clonidine

Oral

-adrenergic blocking agents may exacerbate the rebound hypertension which can follow

the withdrawal of clonidine. If the two drugs are coadministered, the

-adrenergic blocking

agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing

clonidine by

-blocker therapy, the introduction of

-adrenergic blocking agents should be

delayed for several days after clonidine administration has stopped.

Epinephrine

Although

timolol maleate

used alone has little or no effect on pupil size, mydriasis resulting from

concomitant therapy with timolol maleates and epinephrine has been reported occasionally.

Quinidine

Potentiated systemic beta blockade (e.g., decreased heart rate, depression) has been reported during

combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Clinically important changes in standard laboratory parameters were rarely associated with the

administration of systemic timolol maleate. Slight increases in blood urea nitrogen, serum

potassium, serum uric acid and triglycerides and slight decreases in hemoglobin, hematocrit, and

HDL-cholesterol occurred, but were not progressive or associated with clinical manifestations.

9

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The dosage is one drop of Mylan-

Timolol

in the affected eye twice a day.

If needed, concomitant therapy with other agent(s) for lowering intraocular pressure may be given

with Mylan-

Timolol.

The use of two topical beta-adrenergic blocking agents is not recommended

(see WARNINGS AND PRECAUTIONS).

Since in some patients the pressure-lowering response to Mylan-

Timolol

may require a few

weeks to stabilize, evaluation should include a determination of intraocular pressure after

approximately 4 weeks of treatment with Mylan-

Timolol.

If the intraocular pressure is maintained at satisfactory levels, many patients can be placed on

once-a-day therapy. Because of naturally occurring diurnal variations in intraocular pressure,

satisfactory response is best determined by measuring the intraocular pressure at different times

during the day.

How to Transfer Patients from Other Therapy

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 Mylan-

Timolol

started on the following day with one drop of Mylan-

Timolol

in the affected eye(s) twice a day.

When a patient is transferred from a single antiglaucoma agent, other than a topical ophthalmic

beta-adrenergic blocking agent, continue the agent already being used and add one drop of

Mylan-

Timolol

in each affected eye twice a day. On the following day, discontinue the previously

used antiglaucoma agent completely and continue with Mylan-

Timolol

When a patient is transferred from several concomitantly administered antiglaucoma agents,

individualization is required. The physician may be able to discontinue some or all of the other

antiglaucoma agents. Adjustments should involve one agent at a time.

Clinical trials have shown the addition of Mylan-

Timolol

to be useful in patients who respond

inadequately to the maximum tolerable antiglaucoma drug therapy.

Missed Dose

If a dose is missed, it should be applied as soon as possible. However, if it is almost time for the

next dose, the missed dose should be skipped and the next dose should be taken as usual.

10

OVERDOSAGE

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

There have been reports of inadvertent overdosage with

timolol maleate

resulting in systemic

effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness,

headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see also

ADVERSE REACTIONS).

The following additional therapeutic measures should be considered:

Gastric lavage:

If ingested. Studies have shown that timolol does not dialyze readily.

Symptomatic bradycardia

: Use atropine sulfate intravenously in a dosage of 0.25 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 may be considered.

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.

Bronchospasm

: Use isoproterenol hydrochloride. Additional therapy with aminophylline may

be considered.

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.

Heart block (second-or third-degree)

: Use isoproterenol hydrochloride or a transvenous cardiac

pacemaker.

ACTION AND CLINICAL PHARMACOLOGY

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. Timolol maleate combines reversibly with a part of the cell

membrane, the beta-adrenergic receptor, and thus inhibits the usual biologic response that would

occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation

of the beta-adrenergic receptors by catecholamines having beta-adrenergic stimulating (agonist)

activity, whether these originate from an endogenous or exogenous source. Reversal of this

blockade can be accomplished by increasing the concentration of the agonist, which will restore

the usual biologic response.

11

Pharmacokinetics

Timolol maleate (S(-) enantiomer) is significantly metabolized after oral and ophthalmic

administration. The drug and the metabolites (hydroxyethylamino, hydroxyethylglycolamino

derivatives and a third minor metabolite that results from the hydroxylation of a terminal methyl

group on the tertiary butylamino moiety) are excreted primarily via the kidney. Based on

correlation with debrisoquine metabolism, timolol metabolism is mediated primarily by

cytochrome P-450 2D6. Timolol is moderately (<60%) bound to plasma proteins.

Clinical Pharmacology

An 8-week , double-blind, clinical crossover study was done to compare the relative safety and

efficacy of two different formulations of timolol maleate 0.5% ophthalmic solution, Mylan-

Timolol (Mylan Pharmaceuticals ULC) and Timoptic (MSD, Canada). The average intraocular

pressures (IOPs)with Mylan-Timolol ranged from 17.8 to 25.0 (20.64 ± 2.0037) mmHg while with

Timoptic they ranged from 17.7 to 24.4 (20.89 ± 1.6939). No significant adverse effects were

noted with Mylan-Timolol. Analyses of variance comparing the effects on intraocular pressure did

not show statistically significant differences for the two products. The 95 percent clinical

equivalence confidence limit indicates that the performance of Mylan-Timolol approximates that

of Timoptic, within 80% and 125%. In conclusion, this clinical study indicated that Mylan-

Timolol is clinically bioequivalent to Timoptic eye drops.

STORAGE AND STABILITY

Store between 15 and 30°C (59 and 86°F) in a tight, light resistant container. Protect from

freezing.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MYLAN-TIMOLOL (timolol maleate, USP) is supplied as a sterile isotonic, buffered aqueous

solution of timolol maleate equivalent to 2.5 mg (0.25%) or 5 mg (0.5%) timolol per milliliter.

The inactive ingredients include: monobasic and dibasic sodium phosphate, and water for

injection. A preservative, benzalkonium chloride 0.01% is also added.

AVAILABILITY OF DOSAGE FORMS

MYLAN-TIMOLOL (timolol maleate, USP) 0.25%: clear, colourless liquid supplied in white

opaque plastic ophthalmic dispensers of 10 ml, with controlled drop tip.

MYLAN-TIMOLOL 0.5%: clear, colourless liquid supplied in white opaque plastic ophthalmic

dispensers of 10 ml, with controlled drop tip.

12

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Timolol Maleate

Chemical name:

(S)- 1- [(1,1 -dimethylethyl)amino] -3- [ [4-(4-morpholinyl)- 1,2,5-

thiadiazol-3 -yl]oxy] -2-propanol (

Z

)-2-butenedioate( 1:1) (salt)

Molecular formula: C

Molecular mass:

432.49

Structural formula:

Physicochemical properties: Timolol maleate is a beta-adrenergic receptor blocking agent. It

possesses an asymmetric carbon atom in its structure and is provided as the levo isomer. It is a

white odourless, crystalline powder which is soluble in water,

methanol and alcohol.

CLINICAL TRIALS

Comparative Pharmacodynamic Study

An 8-week , double-blind, clinical crossover study was done to compare the relative safety and

efficacy of two different formulations of timolol maleate 0.5% ophthalmic solution, Mylan-

Timolol (Mylan Pharmaceuticals ULC) and Timoptic (MSD, Canada). The average intraocular

pressures (IOPs)with Mylan-Timolol ranged from 17.8 to 25.0 (20.64 ± 2.0037) mmHg while with

Timoptic they ranged from 17.7 to 24.4 (20.89 ± 1.6939). No significant adverse effects were

noted with Mylan-Timolol. Analyses of variance comparing the effects on intraocular pressure did

not show statistically significant differences for the two products. The 95 percent clinical

equivalence confidence limit indicates that the performance of Mylan-Timolol approximates that

13

of Timoptic, within 80% and 125%. In conclusion, this clinical study indicated that Mylan-

Timolol is clinically bioequivalent to Timoptic eye drops.

Timolol maleate

was generally well tolerated and produced fewer and less severe side effects than

either pilocarpine or epinephrine. Bradycardia was reported with

timolol maleate

(see

WARNINGS AND PRECAUTIONS). At trough (12 hours post-dose), the mean reduction was 3.6

beats/minute. At two hours post-dose, the mean reduction in heart rate was 5 beats/minute.

Timolol maleate

has also been used in patients with glaucoma wearing conventional hard contact

lenses, and has generally been well tolerated.

Timolol maleate

has not been studied in patients

wearing lenses made with materials other than polymethylmethacrylate.

14

DETAILED PHARMACOLOGY

Timolol maleate

reduces elevated and normal intraocular pressure whether or not associated with

glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of

glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the

likelihood of glaucomatous visual field loss and optic nerve damage.

Onset of action of timolol maleate is usually rapid, occurring approximately 20 minutes after

topical application on the eye. Maximum reduction of intraocular pressure occurs in one to two

hours. Significant lowering of intraocular pressure has been maintained for as long as 24 hours

with 0.25% or 0.5% Ophthalmic Solution

timolol maleate

twice a day. Repeated observations over

a period of three years indicate that the intraocular pressure-lowering effect of

timolol maleate

well maintained.

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have

significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic

(membrane-stabilizing) activity.

The precise mechanism of action of timolol maleate in lowering intraocular pressure is not

clearly established at this time, although a fluorescein study and tonography studies indicate 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, timolol maleate reduces

intraocular pressure with little or no effect on accommodation or pupil size. Thus, 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.

When changing patients from miotics to

timolol maleate

a refraction might be necessary when

these effects of the miotic have passed.

TOXICOLOGY

Ocular Effects

No adverse ocular effects were observed in rabbits and dogs administered

timolol maleate

topically

in studies lasting one and two years respectively.

15

Acute Toxicity (LD

50

)

Species and Age

Sex

Route of Administration

LD

50

mg/kg

Oral

1190

Mouse (A)

Intravenous

Subcutaneous

1040

Oral

Oral

Rat (YA)

Oral (Fed)

1800

Intraperitoneal

Intraperitoneal

Oral

1040

Rat (W)

Oral

Intraperitoneal

Oral

Rat (I)

Subcutaneous

Oral

Rabbit (A)

Subcutaneous

(A)=Adult;(YA)=Young Adult; (W)=Weanling;(I)=Infant

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 Interactions 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 influence on the toxicity of timolol maleate. Timolol maleate had no effect on the

hypoprothrombinemia induced by bishydroxycoumarin in the dog.

Subacute Toxicity

In rats treated with 100 to 400 mg/kg/day for seven weeks, excessive salivation seen 5 to 10

minutes after dosing had 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

ptyalism, muscle tremors and transient pale extremities.

In dogs, doses of 200 mg/kg/day 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

16

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 of 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.

Tumorigenic Tests

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

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 basis). Timolol caused dose-related elevations of

serum prolactin in female mice at doses of 100 mg/kg/day or more, but only very slight transient

elevations were found in male mice at doses of 500 mg/kg/day. Since numerous studies have

demonstrated that drugs which cause elevations of serum prolactin are associated with mammary

tumors in rodents, the mammary tumors 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.

Reproductive Studies

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.

17

BIBLIOGRAPHY

Berke SJ, Bellows AR, Shingleton BJ, Richter CU, Hutchinson BT. Chronic and recurrent

choroidal detachment after glaucoma filtering surgery. Ophthalmol 1987;94(2):154-62.

Dinai Y, Sharir M, Navey (Floman) N, Halkin H. Bradycardia induced by interaction between

quinidine and ophthalmic timolol. Ann Intern Med 1985;103(6):890-1.

Edeki TI, He H, Wood AJJ. Pharmacogenetic explanation for excessive

-blockade following

timolol eye drops. JAMA 1995;274(20):1611-3.

Higginbotham EJ. Topical

-adrenergic antagonists and quinidine: A risky interaction. Arch

Ophthalmol 1996;114(6):745-6.

Kaila R, Huupponen R, Karhuvaara S, Havula P, Scheinin M, Lisalo E, Salminen L.

Blocking effects of timolol at low plasma concentrations. Clin Pharmacol 1991;49(1):53-8.

Katz IM, Hubbard WA, Getson AJ, Gould LA. Intraocular pressure decrease in normal

volunteers following timolol ophthalmic solution. Invest Ophthalmol 1976;15(6):489-92.

Katz IM, Kulaga SF, Gould AL, Miller IM, Clineschmidt CM, Wittreich JM. Long-term

tolerability and efficacy of timolol ophthalmic solution. Glaucoma 1987;9:84-8.

Mackie JA, Seal DV, Pescod JM. Beta-adrenergic receptor blocking drugs: tear lysozyme

and immunological screening for adverse reaction. Br J Ophthalmol 1977; 61:354-9.

Rozier A, Mazuel C, Grove J, Plazonnet B. GELRITE: A novel, ion-activated,

in situ

Gelling

polymer for ophthalmic vehicles. Effect on bioavailability of timolol. Intl J Pharmaceut

1989;57:163-68.

Samples JR, Meyer SM. Use of ophthalmic medications in pregnant and nursing women. Am

J of Ophthalmol 1988;106(5):616-23.

Toogood JH. Beta-blocker therapy and the risk of anaphylaxis. Can Med Assoc J 1987;

136(9):929-33.

Vela MA, Campbell DG. Hypotony and ciliochoroidal detachment following pharmacologic

aqueous suppressant therapy in previously filtered patients. Ophthalmol 1985;92(1):50-7.

Yablonski ME, Zimmerman TJ, Waltman SR, Becker B. A fluorophotometric study of the

effect of topical timolol on aqueous humor dynamics. Exp Eye Res 1978;27:135-42

Zimmerman TJ, Harbin R, Pett M, Kaufman HE. Timolol and facility of outflow. Invest

Ophthalmol Vis Sci 1977; 16(7): 623-4.

18

Zimmerman TJ, Kaufman HE. Timolol a

-adrenergic blocking agent for the treatment of

glaucoma. Arch Ophthalmol 1977;95 :601-4.

Zimmerman TJ, Kaufman HE. Timolol: A new drug for the treatment of Glaucoma?

Symposium on Ocular Therapy 1977;10:69-76.

Zimmerman TJ, Kaufman HE. Timolol: Dose response and duration of action. Arch

Ophthalmol 1977;95:605-7.

Zimmerman TJ. Timolol maleate - a new glaucoma medication? Invest Ophthalmol Vis Sci

1977; 16(8):687-8.

19. Product Monograph for

Timoptic

, revised May 4, 2007, Control No. 112236. Merck

Frosst Canada Ltd.

IMPORTANT: PLEASE READ

19

PART III: CONSUMER INFORMATION

Pr

Mylan-Timolol

Timolol maleate, USP

This leaflet is part III of a three-part "Product Monograph"

published when

Mylan-Timolol

was approved for sale in

Canada and is designed specifically for Consumers. This

leaflet is a summary and will not tell you everything about

Mylan-Timolol

. Contact your physician or pharmacist if you

have any questions about the drug.

ABOUT THIS MEDICATION

ABOUT THIS MEDICATION

What the medication is used for:

Mylan-Timolol

is the brand name for the medication

imolol

maleate available

only on prescription

through your physician.

Mylan-Timolol

is an ophthalmic solution of a beta- blocking

drug which lowers the pressure in the eye for conditions such

as glaucoma and ocular hypertension and is only available

through a prescription by your physician.

Remember

- This medicine is prescribed for the particular

condition that you have.

Do not give this medicine to other

persons, nor use it for any other condition.

What it does:

The active ingredient timolol maleate is a beta-blocking drug. It

helps lower the pressure in the eye.

When it should not be used:

Do not use

Mylan-Timolol

if you:

are allergic to any of its components

have asthma or have ever had asthma

have chronic obstructive lung disease

have certain heart diseases or conditions

are breast feeding or intend to breast feed.

What the medicinal ingredient is:

Timolol maleate

What the important nonmedicinal ingredients are:

The inactive ingredients include: monobasic and dibasic

sodium phosphate, and water for injection. A preservative,

benzalkonium chloride 0.01% is also added.

What dosage forms it comes in:

MYLAN-TIMOLOL (

imolol maleate USP) is supplied as a

sterile isotonic, buffered aqueous solution of timolol maleate

equivalent to 2.5 mg (0.25%) or 5 mg (0.5%) timolol per

milliliter.

MYLAN-TIMOLOL (

imolol maleate USP) 0.25%: clear,

colourless liquid supplied in white opaque plastic ophthalmic

dispensers of 10 ml, with controlled drop tip.

MYLAN-TIMOLOL 0.5%: clear, colourless liquid supplied

in white opaque plastic ophthalmic dispensers of 10 ml, with

controlled drop tip.

WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS

This medicine may not be suitable for some patients. So, tell your

physician if you think

any

of the following applies to you:

If you have any medical problems now or have had any in

the past, especially asthma and other lung problems or heart

problems;

If you have any allergies to any medications;

Mylan-Timolol

contains benzalkonium chloride as a

preservative. This preservative may be absorbed by soft

contact lenses. If you wear soft contact lenses, consult your

physician before using

Mylan-Timolol.

Do not administer

while wearing (soft) contact lenses. Remove lenses before

application and reinsert no earlier than 15 minutes after use.

If you had past thyroid problems.

If you had past eye problems such as choroidal detachment.

If you had problems or develop problems with blood flow to

the brain.

If you are pregnant or intend to become pregnant.

If you are breast feeding or intend to breast feed. Timolol

has been detected in human breast milk. Discuss with your

physician.

Mylan-Timolol

IS NOT RECOMMENDED FOR CHILDREN.

INTERACTIONS WITH THIS MEDICATION

NTERACTIONS WITH THIS MEDICATION

Your physician also needs to know about drugs (including eye

drops) that you are using or plan to use, including drugs obtained

without a prescription. This is particularly important if you

are taking medicine to lower blood pressure or to treat heart

disease, or depression including beta-blockers such as atenolol,

epinephrine, quinidine, calcium channel blockers or

catecholamine depleting drugs such as reserpine.

PROPER USE OF THIS MEDICATION

PROPER USE OF THIS MEDICATION

Read the following information carefully.

If you need any

explanations, or further information, ask your physician or

pharmacist.

Do not start taking any other medicines unless you have

discussed the matter with your physician or pharmacist.

If you suspect that

Mylan-Timolol

is causing an allergic

reaction (for example, skin rash or redness and itching of the

eye), stop its use and contact your physician as soon as

possible.

If you develop any eye irritation or any new eye problems

such as redness of the eye or swelling of the eyelids, contact

IMPORTANT: PLEASE READ

20

your physician immediately.

If you are using

Mylan-Timolol

with another eyedrop, the

drops should be instilled at least 10 minutes apart.

Do not change the dosage of the drug without consulting

your physician. If you must stop treatment, contact your

physician immediately.

Do not allow the tip of the container to touch the eye or areas

around the eye. It may become contaminated with bacteria

that can cause eye infections leading to serious damage of the

eye, even loss of vision. To avoid possible contamination of

the container, keep the tip of the container away from contact

with any surface.

Contact your physician without delay if you have ocular

surgery or develop a condition that was not present at the

time this medication was prescribed (eg. trauma, an infection,

etc.).

Usual Adult dose:

The appropriate dosage and duration of treatment will be established

by your physician.

The usual dose is one drop in the affected eye(s) in the morning

and in the evening.

Overdose:

If you put too many drops in your eye or swallow the contents of

the bottle, immediately contact your doctor, hospital emergency

department or regional Poison Control Centre.

Missed Dose:

It is important to apply

Mylan-Timolol

as prescribed by your

physician. If you miss a dose, apply it as soon as possible. However,

if it is almost time for the next dose, skip the missed dose and go

back to your regular dosing schedule. Do not double dose.

INSTRUCTIONS FOR USE

1. After receiving your prescription for Mylan-Timolol,

carefully read the dosage instructions on the outer box.

2. After removing the cap from the product, turn the bottle upside

down. Position bottle over the affected eye.

3. Use your index finger to lightly apply pressure to the bottom of

the bottle until your metered dose drop is dispensed. Repeat as

necessary.

4. Once dosage is completed, re-apply cap. Protect from freezing,

ensure storage temperature is between 15°C and 30°C.

If you have any adverse reactions please contact your local

pharmacist or your family physician.

DO NOT TOUCH YOUR EYE OR EYELID WITH

THE DROPPER TIP.

Ophthalmic medications, if handled improperly, can become

contaminated by common bacteria known to cause eye

infections. Serious damage to the eye and subsequent loss of

vision may result from using contaminated ophthalmic

medications. If you think your medication may be

contaminated, or if you develop an eye infection, contact your

physician immediately concerning continued use of this

bottle.

The dispenser tip is designed to provide a single drop;

therefore, do NOT enlarge the hole of the dispenser

tip.

After you have used all doses, there will be some

Mylan-Timolol

left in the bottle. You should not be

concerned since an extra amount of

Mylan-Timolol

been added and you will get the full amount of

Mylan-

Timolol

that your physician prescribed.

Do not attempt to remove excess medicine from the

bottle.

Tell your physician if you wear contact lenses.

Depending on the type of lense, your physician may

advise that you re-insert your contact lenses not

earlier than 15 minutes after application of

Mylan-

Timolol

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Any medicine may have unintended or undesirable

effects, so-called side effects. Although not all of these

side effects may occur, if they do occur, you may

need medical attention.

You may experience eye symptoms such as

burning and stinging, dry eyes, redness of the eye,

foreign body sensation or visual changes, such as

double vision.

IMPORTANT: PLEASE READ

21

Other side effects may also occur rarely, and

some of these may be serious. These may

include shortness of breath.

Timolol maleate has been reported rarely to increase

muscle weakness in some patients with myasthenia

gravis.

Your physician or pharmacist has a complete list of

the possible side effects from this medication. Please tell

your physician or pharmacist promptly about any

unusual symptom.

There are side effects of

timolol maleate

that may affect some

patients’ ability to drive and use machines.

DO ABOUT THEM

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Talk with your

physician or

pharmacist

Symptom / effect

Only if

severe

In all

cases

Stop

taking

drug and

call your

physician

or

pharmacis

t

Uncommon slow heartbeat

Heart effects

such as

irregular

heartbeat, heart

block, low blood

pressure

Rare

Allergic reactions

with symptoms

such as

swelling of the

mouth and

throat,

shortness of

breath, hives,

severe itching and

rash

This is not a complete list of side effects. For any

unexpected effects while taking

Mylan-Timolol,

contact

your physician or pharmacist.

Store between 15 and 30°C (59 and 86°F) in a tight, light

resistant container. Protect from freezing.

KEEP ALL MEDICINES OUT OF REACH OF

CHILDREN.

REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions associated with

the use of health products to the Canada Vigilance Program by

one of the following 3 ways:

Report online at www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete the Canada Vigilance Reporting Form and:

Fax toll-free to 1-866-678-6789, or

Mail to: Canada Vigilance Program

Health Canada

Postal Locator 0701C

Ottawa, ON K1A 0K9

Postal paid labels, Canada Vigilance Reporting Form and the

adverse reaction reporting guidelines are available on the

MedEffect

Canada Web site at

www.healthcanada.gc.ca/medeffect

NOTE: Should you require information related to the

management of the side effect contact your health professional.

The Canada Vigilance Program does not provide medical

advice.

MORE INFORMATIONS

This document plus the full product monograph, prepared for

health professionals can be found by:

contacting the sponsor, Mylan Pharmaceuticals ULC, at: 1-800-

575-1379, or

downloading from Mylan’s Website at: www.mylan.ca

Please consult your doctor or pharmacist with any questions or

concerns you may have regarding your individual condition.

This leaflet was prepared by Mylan Pharmaceuticals ULC

Etobicoke, Ontario M8Z 2S6.

Issued: July 20, 2010

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