Mylan-Timolol Product Monograph

SUMMARY PRODUCT INFORMATION

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.

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.In 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

β-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 β-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

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

β-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 β-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 β-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.

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.

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.

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 β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the β-adrenergic blocking agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by β-blocker therapy, the introduction of β-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.

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.

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.

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.

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: C₁₃H₂₄N₄O₃S.C₄H₄O₄

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

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.

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 is 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.

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 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

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.

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