Apo-Timop Gel (Apotex, 0.5 %) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

APO-TIMOP GEL (timolol maleate ophthalmic gel forming solution) is indicated for the reduction of elevated intraocular pressure.

In clinical trials timolol maleate ophthalmic gel forming solution 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

• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia; sick sinus syndrome; sino-atrial block; second-and third-degree atrioventricular block; overt cardiac failure; cardiogenic shock.
• 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.

WARNINGS AND PRECAUTIONS

General

As with other topically applied ophthalmic drugs, this drug 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 administration.

Cardiovascular

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal’s angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered.

Cardiac failure should be adequately controlled before beginning therapy with timolol maleate ophthalmic gel forming solution. Patient with a history of cardiovascular disease, including cardiac failure, should be watched for signs of deterioration of these diseases, and pulse rates should be monitored.

Due to its negative effect on conduction time, beta blockers should only be given with caution to patients with first degree heart block.

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 ophthalmic solution, USP. These are also potential complications of therapy with timolol maleate ophthalmic gel forming solution.

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 ophthalmic gel forming solution, alternative therapy should be considered.

Patients with severe peripheral circulatory disturbance/disorders (e.g. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.

Endocrine and Metabolism

Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus

Timolol maleate ophthalmic gel forming solution 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.

Masking of 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 unresponsive 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.

OphthalmologicIn 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 ophthalmic gel forming solution is used to reduce elevated intraocular pressure in angle-closure glaucoma they should be used with a miotic and not alone.

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 APO-TIMOP GEL (timolol maleate ophthalmic solution, USP) 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 APO-TIMPO GEL is benzododecinium bromide. This preservative is a quaternary ammonium compound that may be absorbed by soft contact lenses. For timolol maleate ophthalmic gel forming solution, studies have not been done in patients wearing contact lenses. However, in a clinical study, the time required to eliminate 50% of the gel forming solution from the eye was up to 30 minutes.

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.

β-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving APO-TIMOP GEL.

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.

Respiratory

In patients with mild/moderate chronic obstructive pulmonary disease (COPD), Timolol maleate ophthalmic gel forming solution should be used with caution, and only if the potential benefit outweighs the potential risk.

Special Populations

Pregnant Women

Timolol maleate ophthalmic gel forming solution has not been studied in human pregnancy. The use of timolol maleate ophthalmic gel forming solution requires that the anticipated benefit be weighed against possible hazards. 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.

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 ophthalmic gel forming solution is usually well tolerated. The most frequent (6.0%) drug-related complaint in the original clinical trials for timolol maleate ophthalmic gel forming solution was transient blurred vision, lasting from 30 seconds to 5 minutes, following instillation.

Like other topically applied ophthalmic drugs, Timolol maleate ophthalmic gel forming solution is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic betablocking agents. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.

The following possibly, probably, or definitely drug-related adverse reactions occurred with frequency of at least 1% in active treatment controlled clinical trials:

Ocular

Burning and stinging, discharge, foreign body sensation, itching.

The adverse reactions reported for APO-TIMOP (timolol maleate ophthalmic solution, USP) are potential adverse reactions for APO-TIMOP GEL. Please refer to the list below.

Body as a Whole

Headache, asthenia, fatigue.

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, chest pain, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischemia, palpitation, atrioventricular block, cardiac arrest, cardiac failure, 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

Dysgeusia, nausea, diarrhea, dyspepsia, dry mouth, abdominal pain, vomiting.

Hypersensitivity

Signs and symptoms of allergic reactions including anaphylaxis, angioedema, pruritus, urticaria, localized and generalized rash.

Immunologic

Systemic lupus erythematosus.

Integumentary

Alopecia, psoriasiform rash or exacerbation of psoriasis.

Metabolism and nutrition disorders

Hypoglycemia.

Musculoskeletal

Myalgia.

Nervous System/Psychiatric

Depression, insomnia, nightmares, memory loss, increases in signs and symptoms of myasthenia gravis, dizziness, 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 itching, tearing, redness conjunctivitis, conjunctival injection, blepharitis, keratitis, blurred vision, decreased corneal sensitivity, and dry eyes. Visual disturbances: including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, corneal erosion ptosis, and choroidal detachment following filtration surgery (see WARNINGS AND PRECAUTIONS), tinnitus.

Urogenital

Decreased libido, Peyronie’s disease, sexual dysfunction.

Causal Relationship Unknown

The following adverse reactions have been reported but a causal relationship to therapy with APO-TIMOP 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.

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 APO-TIMOP GEL 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 APO-TIMOP GEL is administered together with an oral calcium channel blocker or beta- adrenergic blocking agents, catecholamine-depleting drugs such as reserpine, antiarrhythmics, digitalis glycosides, parasympathomimetics or guanethidine.

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 epinephrine has been reported occasionally.

The potential for mydriasis also exists from concomitant therapy with APO-TIMOP GEL and epinephrine.

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

Clinical Laboratory Test

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.

No specific drug interaction studies have been performed with Timolol maleate ophthalmic gel forming solution.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The usual starting dosage is one drop of 0.25% APO-TIMOP GEL (timolol maleate ophthalmic gel forming solution) 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% APO-TIMOP GEL in the affected eye(s) once a day.

Invert the closed container and shake once before each use. It is not necessary to shake the container more than once.

If needed, concomitant therapy with miotics, epinephrine and systemically administered carbonic anhydrase inhibitors may be given with APO-TIMOP GEL. Other topically applied medications should be administered no less than 10 minutes before APO-TIMOP GEL.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in an increase in local activity.

How to Transfer Patients from Other Therapy

When a patient is transferred from APO-TIMOP (timolol maleate ophthalmic solution) to APO-TIMOP GEL, APO-TIMOP should be discontinued after proper dosing on one day, and treatment with the same concentration of APO-TIMOP GEL 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 APO-TIMOP GEL started on the following day with one drop of 0.25% APO-TIMOP GEL in the affected eye(s) once a day. The dose may be increased to one drop of 0.5% APO-TIMOP GEL once a day if the clinical response is not adequate.

When a patient is transferred from a single antiglaucoma agent, other than a topical ophthalmic beta-adrenergic blocking agent, continue the agent and add one drop of 0.25% APO-TIMOP GEL to each affected eye once a day. On the following day, discontinue the previously used antiglaucoma agent and continue 0.25% APO-TIMOP GEL. If a greater response is required, substitute one drop of 0.5% APO-TIMOP GEL for the 0.25% dosage.

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 APO-TIMOP (timolol maleate ophthalmic solution USP) 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.

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice-daily topical administration of timolol maleate ophthalmic solution

0.5% for 8 days. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.

By comparison to plasma concentrations (10 to 20 ng/mL) following oral 5 mg dose, it was estimated that timolol was approximately 50% bio-available systemically following intraocular administration.

STORAGE AND STABILITY

Store at room temperature 15°C to 30°C. Protect from light and freezing. Discard 28 days after the container is first opened.

DOSAGE FORMS, COMPOSITION AND PACKAGING

APO-TIMOP GEL (timolol maleate ophthalmic gel forming solution) is a sterile, colourless to nearly colourless, slightly opalescent, slightly viscous, aqueous ophthalmic solution. Composition

Each mL of APO-TIMOP GEL 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of APO-TIMOP GEL 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Non-medicinal ingredients: 0.012% benzododecinium bromide (as preservative), gellan gum, mannitol, tromethamine and water for injection.

Gellan gum used in this formulation contains a highly purified anionic heteropolysaccharide. Aqueous solutions of gellan gum form a clear transparent gel at low polymer concentrations in the presence of cations. The concentration of sodium cation in tears is ideally suited to cause gelation of the material when topically instilled in the conjunctival sac. When APO-TIMOP GEL contacts the pre-corneal tear film, it becomes a gel. The vehicle of APO-TIMOP GEL, gellan gum, increases the contact time of the drug with the eye.

Packaging

APO-TIMOP GEL 0.25%, equivalent to 2.5 mg timolol per mL; is supplied in a 11 mL white opaque, low-density polyethylene ophthalmic dispenser bottle and white translucent LDPE dropper tip and a light blue opaque HDPE cap with sealing tape. Each bottle contains 5 mL of APO-TIMOP GEL.

APO-TIMOP GEL 0.5%, equivalent to 5.0 mg timolol per mL; is supplied in a 11 mL white opaque, low-density polyethylene ophthalmic dispenser bottle and white translucent LDPE dropper tip and a light yellow opaque HDPE cap with sealing tape. Each bottle contains 5 mL of APO-TIMOP GEL.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Timolol maleate

Chemical name: (-)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yl) oxy-2-propanol maleate (1:1)

Molecular formula: C₁₃H₂₄N₄0₃S·C₄H₄0₄

Molecular mass: 432.49 g/mol

Structural formula:

Physicochemical Properties:

Description: 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

Clinical studies have shown that the intraocular pressure lowering effect of timolol maleate ophthalmic gel forming solution administered once a day is equivalent to timolol maleate ophthalmic solution administered twice a day. The vehicle of timolol maleate ophthalmic gel forming solution increases the contact time of the drug with the eye.

Timolol maleate ophthalmic solution has also been used in patients with glaucoma wearing conventional hard contact lenses, and has generally been well tolerated. Timolol maleate ophthalmic solution has not been studied in patients wearing lenses made with materials other than polymethylmethacrylate.

Timolol maleate ophthalmic gel forming solution has not been studied in patients wearing contact lenses.

O

N

N

S N

O N

H3C CH3

CH3

OH

OH

OH O

O

H

In a clinical study, the time required to eliminate 50% of the gel forming solution from the eye was up to 30 minutes (see WARNINGS AND PRECAUTIONS).

Timolol maleate ophthalmic solution was generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine. Timolol maleate ophthalmic gel forming solution has a systemic safety profile similar to that of timolol maleate ophthalmic solution, and, as timolol maleate ophthalmic solution, it is well tolerated. Bradycardia was reported less frequently with timolol maleate ophthalmic gel forming solution than with timolol maleate ophthalmic solution. In the three studies comparing timolol maleate ophthalmic gel forming solution 0.5% once a day to timolol maleate ophthalmic solution 0.5% twice a day, timolol maleate ophthalmic gel forming solution did not reduce mean heart rate as much as timolol maleate ophthalmic solution (see WARNINGS AND PRECAUTIONS). At trough (24 hours post-dose timolol maleate ophthalmic gel forming solution, 12 hours post-dose timolol maleate ophthalmic solution), the mean reduction was 0.8 beats/minute for timolol maleate ophthalmic gel forming solution and 3.6 beats/minute for timolol maleate ophthalmic solution; whereas at two hours post-dose, the mean reduction in heart rate was comparable (3.8 beats/minute for timolol maleate ophthalmic gel forming solution and 5 beats/minute for timolol maleate ophthalmic solution).

There was a higher incidence of transient blurred vision following instillation in patients administered timolol maleate ophthalmic gel forming solution.

DETAILED PHARMACOLOGY

APO-TIMOP GEL (timolol maleate ophthalmic solution, USP) 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 with timolol maleate ophthalmic solution whereas it occurs in two to four hours with timolol maleate ophthalmic gel forming solution. Significant lowering of intraocular pressure has been maintained for as long as 24 hours with 0.25% or 0.5% timolol maleate ophthalmic solution twice a day and timolol maleate ophthalmic gel forming solution once a day. Repeated observations over a period of three years indicate that the intraocular pressure-lowering effect of timolol maleate ophthalmic solution 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 ophthalmic solution 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 ophthalmic solution, USP topically in studies lasting one and two years respectively.

No adverse ocular effects were observed in rabbits and monkeys administered timolol maleate ophthalmic gel forming solution topically in studies lasting one month and 12 months, respectively.

Table 1: Acute Toxicity (LD₅₀)

(A) = AduIt; (YA) = Young Adult; (W) = Weanling; (l) = lnfant

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.

The oral LD₅₀ of gellan gum is greater than 5000 mg/kg in rats.

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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