APO-TRAVOPROST-TIMOLOL PQ

2 Recommended Dose and Dosage Adjustment The recommended dosage is one drop in the affected eye(s) once-daily either morning or APO-TRAVOPROST-TIMOLOL PQ Product Monograph Page 5 of 48 evening. The dosage of APO-TRAVOPROST-TIMOLOL PQ should not exceed once-daily since it has been shown that more frequent administration of prostaglandin analogues may decrease the intraocular pressure lowering effect.

Special populations Renal Impairment APO-TRAVOPROST-TIMOLOL PQ has not been studied in patients with renal impairment; caution should be exercised in treating such patients. Use in Pediatric patients (below 18 years) The use of APO-TRAVOPROST-TIMOLOL PQ in pediatric patients <18 years of age is currently not recommended.

The safety and effectiveness of travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) in these patients have not been established. Geriatrics (65 years or above) No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

4 Administration Apply APO-TRAVOPROST-TIMOLOL PQ to the conjunctival sac of the affected eye(s). Nasolacrimal occlusion or gently closing the eyelid for 2 minutes after application is recommended. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.

5 Missed Dose If one dose is missed, treatment should continue with the next dose as normal.

The clinical development of travoprost and timolol ophthalmic solution (polyquaternium-1- preserved) was based on the body of work that had been compiled for the approval of travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved).

These consisted of four Phase 3 clinical trials, one posology study, and one clinical pharmacokinetic study. The clinical development for travoprost and timolol ophthalmic solution (polyquaternium-1- preserved) included three additional studies: one 5-day Phase 1 pharmacokinetic study in healthy subjects (Study C-09-009), one 6-week two-arm pivotal Phase 3 safety/efficacy study (Study C-07-64/C-08-08) and one 12-month Phase 3 single-arm safety study (Study C-09-032) conducted in patients with open-angle glaucoma or ocular hypertension.

The 6-week safety/efficacy study was designed to demonstrate the non-inferiority of travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) compared to travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved).

1 Adverse Reaction Overview In the clinical trials involved in the development of travoprost and timolol ophthalmic solution (polyquaternium-1-preserved), 23 healthy subjects and 349 patients diagnosed with open-angle glaucoma or ocular hypertension were exposed to travoprost and timolol ophthalmic solution (polyquaternium-1-preserved).

8%), which included ocular or conjunctival hyperemia. The majority of patients (91%) who experienced hyperemia of the eye did not discontinue therapy as a result of this reaction. 08%. Seven and four patients discontinued travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) due to ocular adverse reactions in the 12-month safety study, and the pivotal 6-week study, respectively.

In the long-term safety study two cases of mild heart rate decrease and one case of mild hypotension were reported as related to treatment with travoprost and timolol ophthalmic solution (polyquaternium-1-preserved). 2 Clinical Trial Adverse 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 APO-TRAVOPROST-TIMOLOL PQ Product Monograph Page 12 of 48 compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The causal relationship of each adverse event to the study medication was assessed and assigned by the individual study investigator.

The adverse drug reactions in following sections have been assessed to be either definitely related or possibly related to the use of travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) or travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved).

Adverse Drug Reactions in Clinical Trials Providing Medium (6 weeks) or Long-Term (12 Months) Exposure to Travoprost and Timolol Ophthalmic Solution (Polyquaternium-1- Preserved) in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension.

In 2 clinical trials (C-07-64/C-08-08, and C-09-032), 349 patients with open-angle glaucoma or ocular hypertension had medium (6-week; C-07-64/C-08-08) or long-term (12 months; C-09- 032) exposure to travoprost and timolol ophthalmic solution (polyquaternium-1-preserved).

Clinical trial C-07-64/C-08-08 also included 193 patients exposed to travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved). The adverse drug reactions reported in the clinical trials are presented in Table 2 and Table 3.

0 Adverse drug reactions coding to conjunctival or ocular hyperaemia are presented together in the table as ocular hyperaemia. aTwo adverse drug reactions and 1 adverse drug reaction for punctate keratitis were reported in the travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) and travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved) treatment groups, respectively.

An additional single report of punctate keratitis assessed as unrelated to the use of either travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) or travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved) was reported in each treatment group.

All reports of punctate keratitis were reported in female patients. In clinical trial C-07-64/C-08-08, treatment emergent adverse events […]

5% (as APO-TRAVOPROST-TIMOLOL PQ Product Monograph Page 7 of 48 timolol maleate). When APO-TRAVOPROST-TIMOLOL PQ is prescribed, the relevant Product Monographs for travoprost and/or timolol maleate should be consulted. Travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) may result in higher ocular and systemic exposure to travoprost, especially timolol, as compared to travoprost and timolol ophthalmic solution (benzalkonium chloride-preserved) after topical ocular administration (see ACTION AND CLINICAL PHARMACOLOGY).

FOR TOPICAL OPHTHALMIC USE ONLY. Systemic Effects Like other topically applied ophthalmic agents, travoprost and timolol are absorbed systematically. The same adverse reactions found with systemic administration of beta- adrenergic blocking agents may occur with topical administration of travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) due to the beta-adrenergic component, timolol.

For example, severe 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 systemic or ophthalmic administration of timolol maleate (see CONTRAINDICATIONS).

Travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) may result in higher systemic exposure to travoprost, especially timolol, as compared to travoprost and timolol ophthalmic solution (benzanlkonium chloride-preserved) after topical ocular administration (see ACTION AND CLINICAL PHARMACOLOGY).

g. coronary heart disease, Prinzmetal’s angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and for adverse reactions.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning treatment with APO-TRAVOPROST-TIMOLOL PQ. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

, severe forms of Raynaud’s disease or Raynaud’s syndrome).

Concomitant Therapy:

Timolol may interact with other drugs (see DRUG INTERACTIONS). The effect on IOP or the known effects of systemic beta-blockers may be exaggerated when travoprost and timolol ophthalmic solution (polyquaternium-1-preserved) is given to patients already receiving an oral beta-blocking agent.

The response of these patients should be closely observed. The use of two local beta-blockers or two local prostaglandins is not recommended. Driving and Operating Machinery APO-TRAVOPROST-TIMOLOL PQ, as with other similar medications, can potentially cause fatigue and/or drowsiness in some patients.

Patients who engage in hazardous activities should be cautioned regarding the potential for a decrease in mental alertness. APO-TRAVOPROST-TIMOLOL PQ Product Monograph Page 8 of 48 Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines.

If blurred vision occurs after instillation, the patient must wait until the vision clears before driving or using machinery. Endocrine and Metabolism Diabetes Mellitus Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents.

Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia. , tachycardia). Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.

Neurologic Cerebrovascular Insufficiency Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with APO-TRAVOPROST-TIMOLOL PQ, alternative therapy should be considered.

, diplopia, ptosis and generalized weakness). Timolol maleate has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms. Ophthalmologic Travoprost and other prostaglandin analogues have been reported to cause changes to pigmented tissues.

The most frequently reported changes have been increased pigmentation of the iris and periorbital tissue (eyelid) and increased pigmentation and growth of eyelashes. These changes may be permanent. APO-TRAVOPROST-TIMOLOL PQ may gradually change eye color, increasing the amount of brown pigmentation in the iris.

The color change is due to increased melanin content in stromal melanocytes on the iris rather than to an increase in the number of melanocytes, although the exact mechanism of action is unknown at this time. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become browner.

, blue-brown, grey-brown, yellow-brown, and green-brown; however, it has also been observed in patients with brown eyes. The change in iris color occurs slowly […]

5% (as timolol maleate). When APO-TRAVOPROST-TIMOLOL PQ solutionis prescribed, the relevant Product Monographs for travoprost and/or timolol maleate should be consulted. APO-TRAVOPROST-TIMOLOL PQ is contraindicated in patients who: • Are hypersensitive to this drug or to any ingredient in the formulation, including any non- medicinal ingredient, or component of the container.

For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION and PACKAGING. • Have reactive airway diseases, including bronchial asthma. • Have a history of bronchial asthma. • Have severe chronic obstructive pulmonary disease (see WARNINGS AND PRECAUTIONS).

• Have sinus bradycardia. • Have sick sinus syndrome or sino-atrial block. • Have second or third degree atrioventricular block. • Have overt cardiac failure (see WARNINGS AND PRECAUTIONS). • Have cardiogenic shock. APO-TRAVOPROST-TIMOLOL PQ may interfere with the maintenance of pregnancy and should not be used by women during pregnancy or by women attempting to become pregnant.