Latanoprost and Timolol Ophthalmic Solution Product Monograph

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Table of Contents

Sec ons or subsec ons that are not applicable at the me of authoriza on are not listed.

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

NONE AT THE TIME OF MOST RECENT AUTHORIZATION ............................................................................................. 2

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

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

1. 1.

   INDICATIONS ...................................................................................................................................................... 4

   1.1 PEDIATRICS ........................................................................................................................................................... 4 1.2 GERIATRICS ........................................................................................................................................................... 4

2. 2. CONTRAINDICATIONS ......................................................................................................................................... 4
3. 4.

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

   4.1 DOSING CONSIDERATIONS ........................................................................................................................................ 4 4.2 RECOMMENDED DOSE AND DOSAGE ADJUSTMENT ....................................................................................................... 5 4.4 ADMINISTRATION ................................................................................................................................................... 5 4.5 MISSED DOSE ........................................................................................................................................................ 5

4. 5. OVERDOSAGE ..................................................................................................................................................... 5
5. 6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ........................................................................ 6
6. 7.

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

   7.1 SPECIAL POPULATIONS .......................................................................................................................................... 11

   7.1.1 Pregnant Women ....................................................................................................................................... 11 7.1.2 Breast-feeding ............................................................................................................................................ 12 7.1.3 Pediatrics .................................................................................................................................................... 12

7. 8.

   ADVERSE REACTIONS ........................................................................................................................................ 12

   8.1 ADVERSE REACTION OVERVIEW .............................................................................................................................. 12 8.2 CLINICAL TRIAL ADVERSE REACTIONS ....................................................................................................................... 12 8.5 POST-MARKET ADVERSE REACTIONS ........................................................................................................................ 16

8. 9.

   DRUG INTERACTIONS ....................................................................................................................................... 18

   9.2 DRUG INTERACTION OVERVIEW .............................................................................................................................. 18 9.4 DRUG-DRUG INTERACTIONS ................................................................................................................................... 19 9.5 DRUG-FOOD INTERACTIONS ................................................................................................................................... 20 9.6 DRUG-HERB INTERACTIONS.................................................................................................................................... 20 9.7 DRUG-LABORATORY TEST INTERACTIONS .................................................................................................................. 20

9. 10.

   CLINICAL PHARMACOLOGY........................................................................................................................... 20

   10.1 MECHANISM OF ACTION........................................................................................................................................ 20

   10.3 PHARMACOKINETICS ............................................................................................................................................. 20

10. 11. STORAGE, STABILITY AND DISPOSAL ............................................................................................................. 23
11. 12. SPECIAL HANDLING INSTRUCTIONS .............................................................................................................. 23

PART II: SCIENTIFIC INFORMATION ............................................................................................................................ 24

1. 13. PHARMACEUTICAL INFORMATION ............................................................................................................... 24
2. 14.

   CLINICAL TRIALS ........................................................................................................................................... 25

   14.1 CLINICAL TRIALS BY INDICATION............................................................................................................................... 25

3. 15. MICROBIOLOGY ............................................................................................................................................ 28
4. 16. NON-CLINICAL TOXICOLOGY ......................................................................................................................... 28
5. 17. SUPPORTING PRODUCT MONOGRAPH ......................................................................................................... 32

MEDICATION INFORMATION ..................................................................................................................................... 33

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE ................................................................................. 33

PART I: HEALTH PROFESSIONAL INFORMATION

1. INDICATIONS

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION (latanoprost and molol maleate) is indicated for the reduc on of intraocular pressure (IOP) in pa ents with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-adrenergic blocking agents, prostaglandins, or other IOP lowering agents AND when the use of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION (the combina on drug) is considered appropriate.

1.1 Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indica on for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics: Based on the data submi ed and reviewed by Health Canada, there is no overall difference in the safety and efficacy of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION use in the geriatric pa ent popula on.

2. CONTRAINDICATIONS

Latanoprost and molol maleate is contraindicated in pa ents with:

• reac ve airway disease including bronchial asthma, a history of bronchial asthma, or severe chronic obstruc ve pulmonary disease.
• sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker, overt cardiac failure, or cardiogenic shock.
• known hypersensi vity to this drug or to any ingredient in the formula on, including any non-medicinal ingredient, or component of the container. For a complete lis ng, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4. DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• The use of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION may be considered in pa ents who require both molol and latanoprost. It has not been fully inves gated whether pa ents who are adequately controlled with molol twice daily plus latanoprost

  once daily will be effec vely controlled with latanoprost and molol maleate once daily. The IOP lowering effect of latanoprost and molol maleate once daily may be less than that seen with the concomitant administra on of molol twice daily and latanoprost once daily based on the results from a short term clinical trial. For details of informa on obtained from the clinical trial, please refer to the 14 CLINICAL TRIALS sec on.

• LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION contains benzalkonium chloride which may be absorbed by contact lenses. Several contact lens soaking solu ons contain thimerosal which may also form a precipitate with benzalkonium chloride (see 9.4 Drug-Drug Interac ons) Therefore, contact lenses should be removed before installa on of the eye drops and may be reinserted a er 15 minutes.
• LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should not be used to ini ate therapy.

4.2 Recommended Dose and Dosage Adjustment

The recommended adult (including the elderly) dosage of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION (latanoprost and molol maleate) is one drop in the affected eye(s) once daily.

Health Canada has not authorized an indica on for pediatric use (see 7.1.3 Pediatrics).

4.4 Administration

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorp on is reduced. This may result in a decrease in systemic side effects and an increase in local ac vity.

4.5 Missed Dose

If one dose is missed, treatment should con nue with the next dose as normal.

5. OVERDOSAGE

There is no human data available on overdosage with LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION.

Symptoms of systemic molol overdosage are: bradycardia, hypotension, bronchospasm, and cardiac arrest. If such symptoms occur, treatment should be symptoma c and suppor ve. Studies have shown that molol is not readily dialyzable.

Apart from ocular irrita on and conjunc val or episcleral hyperemia, the ocular effects of latanoprost administered at high doses are not known. Intravenous infusion of up to 3 mcg/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 mcg/kg caused nausea, abdominal pain, dizziness, fa gue, hot flashes, and swea ng. These events were mild to moderate in severity and resolved without treatment within 4 hours a er termina ng the infusion.

If overdose with LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION occurs, treatment should be symptoma c.

If LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is accidentally ingested the following informa on may be useful: One bo le contains 125 mcg latanoprost and 12.5 mg molol. Both molol and latanoprost are extensively metabolized in the liver. In fact, more than 90% of latanoprost is metabolized during the first pass through the liver.

6. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composi on and Packaging

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is a sterile, isotonic, buffered, clear and colourless aqueous solu on. One drop contains approximately 1.5 mcg of latanoprost and 150 mcg of molol. LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is intended for topical administra on on the eye.

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is supplied in a 5 mL plas c ophthalmic dispenser bo le with a dropper pand screw cap.

For management of a suspected drug overdose, contact your regional poison control centre.

Each bo le contains 2.5 mL of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION corresponding to approximately 80 drops of solu on.

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is supplied as a sterile, isotonic, buffered, clear and colourless aqueous solu on with a pH of approximately 6.0 and an osmolality of approximately 290 mOsmol/kg. Each mL contains 50 micrograms (mcg) of latanoprost and 5 mg of molol (6.83 mg molol maleate).

Non-medicinal ingredients: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injec on. Benzalkonium chloride 0.02% is added as a preserva ve. If required, the pH of the solu on is adjusted with hydrochloric acid and/or sodium hydroxide.

7. WARNINGS AND PRECAUTIONS

General

There have been reports of bacterial kera s associated with the use of mul ple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by pa ents who, in most cases, had a concurrent corneal disease or a disrup on of ocular epithelial surface (see PATIENT MEDICATION INFORMATION).

There is no or limited experience with latanoprost in inflammatory, neovascular, chronic angle closure or congenital glaucoma, open angle glaucoma in pseudophakic pa ents and pigmentary glaucoma.

Concomitant therapy: LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION may interact with other drugs (see 9.4 Drug-Drug Interac ons). The effect on intraocular pressure or the known effects of systemic beta-adrenergic blocking agents may be exaggerated when LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION is given to pa ents already receiving an oral beta-blocking agent. The use of two local beta-adrenergic blocking agents is not recommended. There have been reports of paradoxical eleva ons in IOP following the concomitant ophthalmic administra on of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin deriva ves is not recommended.

Systemic Effects: Like other topically applied ophthalmic agents, is absorbed systemically. Due to the beta-adrenergic component molol, the same types of cardiovascular, pulmonary and other adverse reac ons seen with systemic beta-adrenergic blocking agents may occur including aggrava on of Prinzmetal’s angina, aggrava on of peripheral and central circulatory disorders, bradycardia, and hypotension.

Incidence of systemic adverse drug reac ons a er topical ophthalmic administra on is lower than for systemic administra on. The systemic absorp on can be reduced by using nasolacrimal occlusion or closing the eyelids for 2 minutes (see 4.4 Administra on).

Cardiovascular

Cardiac reac ons: Death associated with cardiac failure has been reported. Cardiac failure should be adequately controlled before beginning treatment. Pa ents with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. At the first sign of cardiac failure, LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be discon nued. Due to its nega ve effect on conduc on me, beta-adrenergic blocking agents should only be given with cau on to pa ents with first degree heart block.

Vascular Disorders: Pa ents with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with cau on.

Driving and Opera ng Machinery

In common with other eye prepara ons, installa on of eye drops may cause transient blurring of vision.

Endocrine and Metabolism

Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with cau on in pa ents subjected to spontaneous hypoglycemia or to diabe c pa ents (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.

Thyrotoxicosis: Therapy with beta-adrenergic blocking agents may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-adrenergic blocking agent therapy may precipitate a worsening of symptoms.

Hepa c/Biliary/Pancrea c

Latanoprost and molol maleate has not been studied in pa ents with hepa c impairment and therefore should be used with cau on in such pa ents.

Neurologic

Muscle Weakness: Beta-adrenergic blocking agents have been reported to rarely increase muscle weakness in some pa ents with myasthenia gravis or myasthenic symptoms (e.g. diplopia, ptosis, generalized weakness).

Ophthalmologic

Latanoprost has been reported to cause darkening, thickening and lengthening of eye lashes (see 8.5 Post-Market Adverse Reac ons).

Based on spontaneous reports, very rare cases of darkening of the palpebral skin have been reported with the administra on of latanoprost ophthalmic solu on (see 8.5 Post-Market Adverse Reac ons).

Due to the prostaglandin component latanoprost, LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be used with cau on in pa ents with a history of herpe c kera s. LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be avoided in cases of ac ve herpes simplex kera s and in pa ents with a history of recurrent herpe c kera s specifically associated with prostaglandin analogues.

This product contains benzalkonium chloride as a preserva ve, which may be absorbed by so contact lenses. Remove contact lenses before administra on of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION. Contact lenses may be reinstalled 15 minutes a er administering LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION.

Ophthalmic beta-adrenergic blocking agents may induce dryness of eyes. These agents should be used prescribed with cau on in pa ents with corneal diseases.

Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solu on. These reports have mainly occurred in aphakic pa ents, in pseudophakic pa ents with a torn posterior lens capsule, or in pa ents with known risk factors for macular edema. LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be used with cau on in these pa ents.

Choroidal detachment a er filtra on procedures has been reported with the administra on of ocular hypotensive agents.

Changes to Pigmented Tissues: Latanoprost, the prostaglandin component contained in LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION, may gradually change the eye color, by increasing the amount of brown pigment 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. Typically the brown pigmenta on around the pupil spreads concentrically towards the periphery in affected eyes, but the en re iris or parts of it may become more brownish. The change in iris colour occurs slowly and may not be no ceable for several months to years. The long term effects on the melanocytes and the consequences of poten al injury to the melanocytes and/or deposi on of pigment granules to other areas of the eye is currently

unknown. Pa ents should be examined regularly and, depending on the clinical situa on, treatment may be stopped if increased iris pigmenta on ensues.

This effect has predominantly been seen in pa ents with mixed colored irides (i.e. blue/gray- brown, green-brown, or yellow-brown). In pa ents with homogeneously blue, gray, green or brown eyes, the change has only rarely been seen during two years of treatment in clinical trials. The change in iris color occurs slowly, and may not be no ceable for several months to years. Pa ents should be informed of the possibility of iris color change. Pa ents who are expected to receive treatment in only one eye should be informed about the poten al for increased brown pigmenta on in the treated eye and thus, permanent heterochromia between the eyes. The increased pigmenta on is permanent.

There is no evidence of melanin from iris melanocytes in trabecular meshwork in clinical studies which supports the lack of hyperpigmenta on of the trabecular meshwork as a result of latanoprost treatment. In addi on, no difference in iridial pigment epithelial melanin content has been observed between the latanoprost-treated eyes with increased iris pigmenta on and untreated eyes from quan ta ve morphologic inves ga on of iridial specimens following colour change. Histopathologically, the increase in pigmenta on was limited to a minor increase in the size of the melanin granules in the iris stroma.

Closed Angle Glaucoma: LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should not be used alone in the treatment of acute closed angle glaucoma. In pa ents with closed angle glaucoma, the immediate objec ve of treatment is to reopen the angle. This requires constric ng the pupil. Latanoprost and Timolol Maleate have li le or no effect on the pupil.

Peri-Opera ve Considera ons

A gradual withdrawal of beta-adrenergic blocking agents prior to major surgery should be considered. Beta-adrenergic blocking agents impair the ability of the heart to respond to beta- adrenergically mediated reflex s muli, which may augment the risk of general anesthesia in surgical procedures. Protracted severe hypotension during anesthesia and difficulty restar ng and maintaining the heartbeat have been reported. During surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Surgical anaesthesia: Beta-blocking ophthalmological prepara ons may block systemic beta- agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the pa ent is receiving molol.

Renal

Latanoprost and molol maleate has not been studied in pa ents with renal impairment and therefore should be used with cau on in such pa ents.

Reproduc ve Health: Female and Male Poten al

• Fer lity

Latanoprost has not been found to have any effect on male or female fer lity in animal studies. Reproduc on and fer lity studies of molol maleate in rats demonstrated no adverse effect on male or female fer lity at doses up to 21,000 mes the systemic exposure following the maximum recommended human ophthalmic dose.

Respiratory

Respiratory Reac ons: Severe respiratory reac ons including death due to bronchospasm in pa ents with asthma and rarely death associated with cardiac failure have been reported following administra on of beta-adrenergic blocking agents.

Respiratory Disorders: Due to the beta-adrenergic component molol maleate, LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be used with cau on, in pa ents with mild/moderate chronic obstruc ve pulmonary disease (COPD) and only if the poten al benefit outweighs the poten al risk.

Sensi vity / Resistance

Anaphylac c Reac ons: While taking beta-adrenergic blocking agents, pa ents with a history of atopy or severe anaphylac c reac on to a variety of allergens may be more sensi ve to repeated challenge. These could include environmental, diagnos c or therapeu c allergens. Such pa ents may be unresponsive to the usual doses of adrenaline used to treat anaphylac c reac ons.

7.1 Special Populations

7.1.1 Pregnant Women

No reproduc on toxicity studies have been conducted with latanoprost and molol maleate. Embryofetal development studies with latanoprost have been performed in rats and rabbits. Latanoprost and/or its metabolites cross the placenta of rats. In rabbits, latanoprost caused embryofetal toxicity characterized by increased incidences of late resorp on and reduced fetal weight at 5 mcg/kg/day IV and total li er resorp on at > 50 mcg/kg/day IV. No embryofetal effects were seen in rabbits at 1 mcg/kg/day IV and in rats at up to 250 mcg/kg/day IV.

Timolol maleate was not teratogenic in mice, rats and rabbits. Embryofetal development studies with molol maleate in mice and rabbits showed no evidence of embryofetal toxicity at oral doses up to 50 mcg/kg/day. At higher doses, increases in resorp ons and fetal varia ons (14 ribs and hypoplas c sternebrae) were no ced in mice (1000 µg/kg/day) and increased resorp on in rabbits (> 90 mcg/kg/day). In rats, delayed ossifica on was seen > 50 mcg/kg/day

and a decreased number of caudal vertebral bodies and arches and an increase in hypoplas c sternebrae were noted at 500 mcg/kg/day.

For addi onal informa on, see 16 NON-CLINICAL TOXICOLOGY.

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be used during pregnancy only if the poten al benefit jus fies the poten al risk to the fetus.

7.1.2 Breast-feeding

There are limited experimental animal and no human data available on the pharmacokine cs of latanoprost lacta on. Latanoprost and its metabolites may pass into breast milk. Timolol maleate has been detected in human milk following oral and ocular administra on. Because of the poten al for serious adverse reac ons from latanoprost and molol maleate in nursing infants, LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION should be used with cau on in nursing women.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of the use of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION in children has not been established; therefore, Health Canada has not authorized an indica on for pediatric use.

8. ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most commonly reported ocular adverse reac ons in controlled clinical trials, that may be associated with combina on therapy of latanoprost and molol maleate were eye irrita on (12.4 %), eye hyperaemia (7.4 %), abnormal vision (6.6 %), conjunc vi s (3.0 %) and corneal disorder (3.0 %) (see 8.2 Clinical Trial Adverse Reac ons). The most commonly reported systemic adverse reac ons in controlled clinical trials, that may be associated with combina on therapy of latanoprost and molol maleate were upper respiratory track infec on (6.1 %), hypertension (3.8 %), influenza-like symptoms (2.5 %) and headache (2.3 %) (see 8.2 Clinical Trial Adverse Reac ons).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific condi ons. The adverse reac on rates observed in the clinical trials; therefore, may not reflect the rates observed in prac ce and should not be compared to the rates in the clinical trials of another drug. Adverse reac on informa on from clinical trials may be useful in iden fying and approxima ng rates of adverse drug reac ons in real-world use.

Latanoprost and molol maleate was generally well tolerated. No adverse events specific to latanoprost and molol maleate have been observed in clinical studies. The adverse events have been limited to those that were reported previously with latanoprost and/or molol maleate.

Latanoprost and molol maleate was evaluated for safety in 394 pa ents with open-angle glaucoma or ocular hypertension in three long-term studies. Two percent (2%) of pa ents discon nued therapy with latanoprost and molol maleate due to adverse events.

Adverse events occurring at a frequency of > 1% in three randomized, double blind compara ve trials (004, 005 and 053) are presented in Tables 2 and 3.

Table 2. Ocular adverse events (AE) that occurred in ≥ 1% of pa ents¹, in any treatment group, by preferred term³

¹ Despite a low frequency of reports, some AEs are included in the lis ng due to the implica on of a poten ally sight-threatening condi on.

² A pa ent is counted only once per preferred term

³ Studies 004 and 005 included a 6 month and 053 a 12 month double-blinded period

⁴ Includes darkening, lengthening and growing of eye lashes

Table 3:

Systemic adverse events (AE) that occurred in ≥1% of pa ents¹, in any of the treatment groups, by body system/preferred term²

¹ A patient is counted only once per preferred term. AEs that occurred in <1 % of the patients but were very similar to an event that did occur in > 1% of the patients (such as “hypertension” and “hypertension aggravated”) are listed. Also, groups of mutually related AEs, where each AE may be reported in < 1%, but together they sum up to > 1% (such as “diabetes mellitus aggravated” and “hyperglycaemia” together with “glucosuria”) are summarised.

² Studies 004 and 005 included a 6 month- and 053 a 12 month double-blinded period

Based on evidence from consecu ve photographs, increased iris pigmenta on was observed in 16-20% of pa ents treated with latanoprost and molol maleate for up to one year. The most frequent findings of increased iris pigmenta on were in the known high-risk eye color groups, i.e. those with green- brown, yellow-brown, and blue/gray-brown irises. In pa ents with homogeneously blue, grey, green or brown eyes, the change was rarely observed. Darkening, thickening and lengthening of eye lashes were observed in 37.4% of pa ents.

8.5 Post-Market Adverse Reactions

The following addi onal adverse events that have been reported with latanoprost and molol eye drops:

Latanoprost

Timolol Maleate (topical formula on)

Cases of corneal calcifica on have been reported very rarely in associa on with the use of phosphate-containing eye drops in some pa ents with significantly damaged corneas.

9. DRUG INTERACTIONS

9.2 Drug Interaction Overview

No specific interac on studies have been performed with latanoprost and molol maleate.

Pa ents who are receiving treatment with LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION and an oral beta-adrenergic blocking agent should be observed for poten al addi ve effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.

There have been reports of paradoxical eleva ons in IOP following the concomitant ophthalmic administra on of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin deriva ves is not recommended.

The poten al exists for addi ve effects resul ng in hypotension, and/or marked bradycardia when molol ophthalmic drops are administered with oral calcium channel blockers, catecholamine-deple ng drugs or beta-adrenergic blocking agents, an arrythmics (including amiodarone and quinidine), digitalis glycosides, parasympathomime cs, narco cs, guanethidine and monoamine oxidase (MAO) inhibitors.

Poten ated systemic beta adrenergic blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxe ne, paroxe ne) and molol.

Although latanoprost and molol maleate alone has li le or no effect on pupil size, mydriasis has occasionally been reported when molol is given with epinephrine.

Beta-adrenergic blocking agents may increase the hypoglycemic effect of an diabe c agents.

In vitro studies have shown that precipita on occurs when eye drops containing thimerosal are mixed with benzalkonium chloride, the preserva ve used in LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION. If such drugs are used they should be administered with an interval of at least 5 minutes between applica ons. Similarly, several contact lens soaking solu ons contain thimerosal (see 4.4 Administra on).

9.4 Drug-Drug Interactions

Table 4 - Established or Poten al Drug-Drug Interac ons

Legend: C = Case Study; CT = Clinical Trial; T = Theore cal

9.5 Drug-Food Interactions

Interac ons with food have not been established.

9.6 Drug-Herb Interactions

Interac ons with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interac ons with laboratory tests have not been established.

10. CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION consists of two components: latanoprost and molol maleate. Each mL of LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION contains latanoprost 50 micrograms and molol maleate 6.8 mg equivalent to 5 mg molol. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of ac on.

Latanoprost is a prostanoid selec ve FP receptor agonist which reduces the IOP by increasing the ou low of aqueous humor. The main mechanism of ac on is increased uveoscleral ou low. In addi on, some increase in ou low facility (decrease in trabecular ou low resistance) has been reported in man. Timolol maleate is a beta1 and beta2 (non-selec ve) adrenergic receptor blocking agent that does not have significant intrinsic sympathomime c, direct myocardial depressant, or local anesthe c (membrane-stabilizing) ac vity. Timolol lowers the IOP by decreasing the forma on of aqueous humor in the ciliary epithelium. The precise mechanism of ac on is not clearly established. The combined effect of these two agents administered as latanoprost and molol maleate once daily results in addi onal intraocular pressure reduc on compared to either component administered alone separately. For details of informa on obtained from Clinical Trials with latanoprost and molol maleate, please refer to 14 CLINICAL TRIALS sec on.

10.3 Pharmacokinetics

Table 5 - Summary of latanoprost Pharmacokine c Parameters in aqueous humor in adults

Table 6 - Summary of latanoprost Pharmacokine c Parameters in plasma in adults

Table 7 - Summary of molol Pharmacokine c Parameters in aqueous humor in adults

Table 8 - Summary of molol Pharmacokine c Parameters in plasma in adults

Latanoprost

Absorp on: Latanoprost is an isopropyl ester prodrug which is inac ve but becomes biologically ac ve a er hydrolysis to the acid of latanoprost. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humor is hydrolysed by esterases during the passage through the cornea. Studies indicate that the maximum concentra on in the aqueous humor, approximately 30 ng/mL, is reached about 2 hours a er topical administra on of latanoprost alone. A er topical ocular administra on, the systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein binding of 87%.

Distribu on: The acid of latanoprost has a small volume of distribu on of 0.16 L/kg.

Metabolism: Latanoprost is an isopropyl ester prodrug which is inac ve but becomes biologically ac ve a er hydrolysis to the acid of latanoprost. The main metabolism occurs in the liver. There is prac cally no metabolism of the acid of latanoprost in the eye. The main metabolites, 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or weak biological ac vity

Elimina on: The acid of latanoprost has a plasma clearance of 0.40 L/h/kg and a rapid half-life in plasma of 17 minutes. The main metabolites, 1,2-dinor and 1,2,3,4- tetranor metabolites, exert no or weak biological ac vity in animal studies and are excreted primarily in the urine.

Timolol

Absorp on: The maximum concentra on of molol in the aqueous humor is reached about one hour a er topical ocular administra on. Part of the dose is absorbed systemically and a maximum plasma concentra on of 1 ng/mL is reached 10-20 minutes a er topical ocular administra on of one drop to each eye once daily (300 mcg /day).

Metabolism: Timolol is extensively metabolized in the liver.

Elimina on: The half-life of molol in plasma is about 6 hours. The metabolites, and unchanged molol, are excreted in the urine.

Latanoprost and molol maleate

No pharmacokine c interac ons between latanoprost and molol have been observed although the aqueous humor concentra ons of the acid of latanoprost tended to be higher 1 to 4 hours a er administra on of the combina on product compared to monotherapy with either latanoprost or molol.

Special Popula ons and Condi ons

Pediatrics: Differences in the pharmacokine cs of latanoprost and molol maleate in this popula on has not been inves gated.

Geriatrics: Differences in the pharmacokine cs of latanoprost and molol maleate in this popula on has not been inves gated.

Sex: Differences in the pharmacokine cs of latanoprost and molol maleate in this popula on has not been inves gated.

Ethnic Origin: Differences in the pharmacokine cs of latanoprost and molol maleate in this popula on has not been inves gated.

Hepa c Insufficiency: No studies have been performed to inves gate the influence of demographic characteris cs on the pharmacokine cs of latanoprost and molol maleate due to the inherent difficul es in measuring the drug concentra ons a er topical administra on on the eyes.

Renal Insufficiency: No studies have been performed to inves gate the influence of demographic characteris cs on the pharmacokine cs of latanoprost and molol maleate due to the inherent difficul es in measuring the drug concentra ons a er topical administra on on the eyes.

1. 11. STORAGE, STABILITY AND DISPOSAL

Store unopened bo le under refrigera on (2°C to 8°C). Protect from light. Once opened, the 5 mL container may be stored at room temperature up to 25°C for 10 weeks. Protect from light.

1. 12. SPECIAL HANDLING INSTRUCTIONS

There are no special handling instruc ons for this drug product.

PART II: SCIENTIFIC INFORMATION

1. 13. PHARMACEUTICAL INFORMATION

Drug Substance

LATANOPROST AND TIMOLOL OPHTHALMIC SOLUTION (latanoprost and molol maleate) contains latanoprost and molol maleate.

Latanoprost:

Proper Name: latanoprost

Chemical Names: 1) Isopropyl-(Z)-7[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5 phenylpentyl]cyclopentyl]-5-heptenoate

1. 2) 5-Heptenoic acid, 7-[3,5-dihydroxy-2-(3-hydroxy- 5-phenylpentyl)cyclopentyl]-1-methylethyl ester, [1R- [1α(Z),2β(R*),3α,5α]]

Molecular formula and molecular mass: C26H40O5 and 432.59 g/mol

Structural Formula:

Physicochemical Proper es:

Physical Form Colourless to slightly yellow oil.

Solubility Very soluble in acetonitrile and freely soluble in acetone, ethanol, ethyl acetate,

isopropanol, methanol and octanol, and prac cally insoluble in water.

Timolol Maleate:

Proper Name: molol maleate

Chemical Name:

(2S)-1-[(1,1- dimethylethyl)amino]-3-[[4-(morpholin-4-yl)-1,2,5- thiadiazol-3-yl]oxy]propan-2-ol (Z)-butenedioate

Molecular formula and molecular Weight: C17H28N4O7S and 432.5 g/mol

Structural Formula:

Physicochemical Proper es:

Physical form White to off-white crystalline powder

Solubility Soluble in water, alcohol and prac cally insoluble in ether.

pH 3.8 - 4.3 (2% in Water)

pKa 9.2

Mel ng Point 200 - 202ºC with decomposi on

14. CLINICAL TRIALS

14.1 Clinical Trials by Indication

Reduc on of intraocular pressure (IOP) in pa ents with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-adrenergic blocking agents, prostaglandins, or other IOP lowering agents

Two 6-month, randomized, double-masked, mul center clinical studies were conducted to compare the IOP-lowering effect of latanoprost and molol maleate dosed once daily to latanoprost 50 mcg/mL dosed once daily and molol 5 mg/mL dosed twice daily.

The inclusion criteria in both studies consisted of adults with a diagnosis of primary open angle glaucoma (72%), ocular hypertension (20%), pigmentary glaucoma (2%), exfolia ve glaucoma (4%) and other (2%). Pa ents enrolled could have been on previous therapy (88%) or not on medica on (12%) and were required to have an IOP of > 25 mmHg if on medica on or

>30 mmHg if not on therapy at enrollment. There was no restric on on the number or type of glaucoma medica ons taken prior to study entry. The distribu on of pa ents at enrollment on glaucoma medica on and not on glaucoma medica on were similar in each of the three treatment groups. Approximately 70% of pa ents were on molol therapy prior to enrollment. In the studies the baseline study visit was preceded by a 2-4 weeks run-in period on molol 5 mg/mL bid.

Table 10 and 11 shows the mean diurnal IOP reduc ons at the end of the treatment latanoprost and molol maleate (FC) and the individual monotherapies for all pa ents. All values are sta s cally significant.

Table 9. Summary of pa ent demographics for clinical trials in the reduc on of intraocular pressure (IOP) in pa ents with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-adrenergic blocking agents, prostaglandins, or other IOP lowering agents

Table 10 - Results of study 004 in the reduc on of intraocular pressure (IOP) in pa ents with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta- adrenergic blocking agents, prostaglandins, or other IOP lowering agents

Table 11 - Results of study 005 in the reduc on of intraocular pressure (IOP) in pa ents with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta- adrenergic blocking agents, prostaglandins, or other IOP lowering agents

Pa ents enrolled could have been on previous therapy (88%) or not on medica on (12%). Analysis on the primary efficacy endpoints for studies 004 and 005 indicate that inclusion or exclusion of pa ents who are not on medica on prior to enrollment (12%) had no influence on sta s cal outcome of efficacy observed in the studies.

In clinical prac ce, the appropriate value of a target IOP (an IOP level that would be considered a clinical success) is determined by the physician for each pa ent. Informa on from the recent Advanced Glaucoma Interven on Study (AGIS) indicates that an IOP of 18 mmHg or less is correlated with reduced progression of visual field defects associated with glaucoma. A responder analysis was performed for the two studies and supports the value of latanoprost and molol maleate over the individual monotherapies as shown in Table 12.

Table 12: Responder* rate within each treatment group for each designated threshold value.

Treatment Groups (%)

* Responder for the analysis was defined as that all IOP measurements for a pa ent were equal to or below the stated threshold value. All values are sta s cally significant.

A short term double blind, controlled, crossover study (n=190) was performed to evaluate Latanoprost and molol maleate fixed combina on (FC) versus the individual monotherapies (latanoprost once daily and molol 5 mg/mL twice daily administered separately, uFC) in maintaining the IOP of well-controlled pa ents on the combina on of the individual monotherapies. In this study pa ents were randomized into one of two treatment sequences, (FC-UFC) or (UFC - FC) with each treatment in the sequence given for 6 weeks. The mean baseline IOP for the groups receiving FC-UFC and UFC -FC treatment sequences was, 17.2 mmHg and 17.1 mmHg respec vely. Results from this short-term crossover study indicates that latanoprost and molol maleate maintained the IOP seen in the popula on at enrollment while the concomitant use of the individual monotherapies resulted in a decrease in the IOP. Overall, the mean IOP a er FC treatment was 17.0 mmHg and was 15.9 mmHg following uFC treatment. The 95% CI for the difference in diurnal IOP between the two treatments a er six weeks of dosing was 0.8 to 1.4 mmHg.

Open-label extensions of these studies were conducted for up to an addi onal 6 months. The IOP-lowering effect of latanoprost and molol maleate was maintained during this period.

There are no data to show the op mal dose of latanoprost and molol in combina on.

15. MICROBIOLOGY

No microbiological informa on is required for this drug product.

16. NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity

Latanoprost and molol maleate

A single subcutaneous dose of 20 mL/kg, corresponding to 1 mg/kg of latanoprost and

100 mg/kg of molol, was well tolerated in rats and the only finding was a local reac on at the site of injec on (thickening of the skin).

Latanoprost

A single oral dose of 50 mg/kg and an intravenous dose of 2 mg/kg were well tolerated in mice and rats. In male dogs given an intravenous infusion of latanoprost, the minimum lethal dose was greater than 680 mcg/kg.

Timolol

The LD50 values a er oral administra on was 1190 mg/kg in mice and 900 mg/kg in rats. The corresponding values a er parenteral administra on were 225 mg/kg (i.v.) and 383 mg/kg (i.p.), respec vely. Infant rats were more sensi ve than adult animals. In rabbits, the maximum nonlethal oral and intravenous doses were 485 mg/kg and 34 mg/kg, and the LD50 values were 347 mg/kg and 16 mg/kg, respec vely.

Repeated Dose Toxicity

Latanoprost and molol maleate

Local toxicity has been inves gated a er twice daily topical applica on in pigmented rabbits for 4 weeks. The daily dose of latanoprost was 3 mcg/eye and that of molol was 300 mcg/eye. No local ocular irrita on or changes at ophthalmological examina ons were found and there were no macroscopic and microscopic altera ons.

Chronic local and systemic toxicity has also been evaluated in pigmented rabbits. One drop once daily ocular administra on, corresponding to 1.5 mcg/eye/day of latanoprost and 150 mcg/eye/day of molol, produced no evidence of local irrita on, and ocular or systemic toxicity, as assessed by ophthalmoscopy, tonometry, pachymetry, clinical chemistry, and complete gross and microscopic examina ons. In conclusion, the applica on of latanoprost and molol ophthalmic solu on to the rabbit eye for 52 weeks was well tolerated.

Latanoprost

Ocular and systemic toxicity of latanoprost has been inves gated in several animal species. Repeated intravenous doses of up to 340 mcg/kg/day for 4 weeks were well tolerated in rats, whereas intravenous doses of 100 mcg/kg/day and above induced hypersaliva on and miosis during infusion followed by vomi ng and some mes liquid feces post-infusion in dogs.

Latanoprost was well tolerated and produced no evidence of ocular or systemic toxicity when administered to rabbits and cynomolgus monkeys at doses of up to 100 mcg/eye/day for 52 weeks and to rhesus monkeys at doses up to 20 mcg/eye for up to 104 weeks. However, in cynomolgus and rhesus monkeys, latanoprost has been shown to induce increased pigmenta on of the iris at doses from 2 mcg/day, with a dose-dependency in onset. An

increase in palpebral fissure was also observed at doses from 6 mcg/eye/day in chronic ocular toxicity studies in monkeys. This could be due to a change in the suppor ve ssue around the eyelids. No changes could be detected histologically in the eyelids affected. This effect is reversible and occurs at doses well above the human clinical dose.

Iris pigmenta on

The increased iridial pigmenta on observed in monkeys and also in humans during chronic ocular treatment with latanoprost is considered to be a class effect of prostaglandins. It is of par cular interest that naturally occurring prostaglandins such as PGF2α and PGE2 also cause increased pigmenta on of the iris in cynomolgus monkeys. It should also be noted that both cynomolgus monkey and human iridial melanocytes express FP receptors in their cell membrane, and since latanoprost is a very selec ve FP receptor agonist, it implies that the effect is mediated by FP receptors in the melanocytes. It has been confirmed that there is no specific uptake of latanoprost in the melanin-containing ssues of the eye.

Studies on monkey and human melanocytes have shown that latanoprost has no prolifera ve effect on ocular melanocytes. In bilaterally sympathectomized rabbits, which were treated unilaterally with latanoprost and developed slightly increased iridial pigmenta on in the treated eye, no difference in the number of melanocytes in iridial sec ons was found between the eyes exhibi ng increased pigmenta on and the control eyes. This confirms the results of in vivo and in vitro studies in primates showing a lack of prolifera ve effect of latanoprost on ocular melanocytes.

In a 104-week ocular toxicity study in rhesus monkeys, the iridial stroma exhibited a more intense pigmenta on of the pigmented cells in all treated groups, but remained morphologically normal at the end of the treatment and recovery periods. A quan ta ve morphometric analysis showed an increase in the number of melanosomes in iridial melanocytes, and an increase in the cell area and ra o of granule area to cell area in the treated eyes when compared to the control eyes. However, in animals treated for 52 weeks following a recovery period of 104 weeks, no significant difference between treated and control eyes were observed at the end of the recovery period. These data suggest a minor modifica on in melanosome number and size with treatment and an apparent tendency towards reversibility a er an extensive recovery period.

Morphological examina on of three iridectomy specimens from pa ents indicated that the eye color change a er long-term topical treatment with latanoprost is more likely produced by increased melanin density per melanocyte, or movement and rearrangement of cells in the ssue than by prolifera on of melanocytes. Thus, there are no indica ons of any toxic effects of latanoprost on the pigment containing cells of the iris. In addi on, results have shown that the increase of pigmenta on is due to increased synthesis or turnover of melanin in the iridial melanocytes, and no prolifera ve changes occur during pigmenta on.

Timolol

In rats, oral administra on of molol for 8 weeks was associated with increased spleen weights and splenic conges on at doses from 400 mg/kg/day, and decreases in body weight gain and mortality at 800 mg/kg/day. No changes were found at these dose levels a er 7 weeks of treatment. In subchronic studies in dogs, oral doses from 100 mg/kg/day caused emesis and renal toxicity, and death occurred at 200 mg/kg/day. Timolol was well tolerated in dogs a er repeated administra on of oral doses up to 25 mg/kg/day for 54 weeks. The only treatment related findings were pharmacologic effects, including decreases in heart rates and slight increases in the PR and QT intervals, at doses from 5 mg/kg/day and above.

Timolol did not cause any adverse ocular effects in rabbits when administered as mul ple daily topical doses up to 6 mg/eye/day for 52 weeks or in dogs a er three mes daily ins lla on at doses up to 1.5 mg/eye/day, five days a week, for 104 weeks.

Carcinogenicity

Latanoprost

No carcinogenic poten al was indicated in rodents a er oral doses of up to 200 mcg/kg/day. At this dose, the maximum plasma concentra ons of acid of latanoprost in mice and rats were at least 50 and 13 mes higher, respec vely, than those in humans a er a clinical dose of latanoprost in both eyes.

Timolol

No evidence of carcinogenicity was observed at oral doses up to 100 mg/kg/day in rats and

50 mg/kg/day in mice, which resulted in systemic exposures of approximately 7000-14000 mes the exposure in humans a er a maximum recommended ophthalmic dose of molol. However, significant increases in adrenal pheochromocytomas were found in male rats administered 300 mg/kg/day. In female mice at 500 mg/kg/day, significant increases were observed in the incidence of benign and malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinomas. The increased incidence of mammary tumors was considered related to a species-specific eleva on in serum prolac n.

Reproduc on and Developmental Toxicology

Latanoprost

Latanoprost has no effects on fer lity and general reproduc ve performance in male and female rats, and no teratogenic poten al in rats or rabbits. No embryotoxicity was observed in rats a er intravenous doses of up to 250 mcg/kg/day. However, latanoprost caused embryofetal toxicity, characterized by an increased incidence of late resorp on and abor on, and by reduced fetal weight, in rabbits when administered intravenously at doses of 5 mcg/kg/day and above, whereas a dose of 1 mcg/kg/day had no effects. The effects on the fetal development are

probably a ributed to a marked luteoly c effect in rabbits, a class effect of prostaglandin F2α and its analogues. However, this effect is minimal in humans.

Timolol

Reproduc on and fer lity studies in rats showed no adverse effects on male or female fer lity at oral doses of 300 and 450 mg/kg/day, respec vely. No teratogenic effects or embryofetal toxicity was observed in mice, rats or rabbits a er oral doses up to 50 mg/kg/day (about

7000 mes the systemic exposure in humans a er a maximum therapeu c dose of molol ophthalmic solu on). Timolol did not cause any effects on peri- and postnatal development in mice and rats when administered orally at doses of up to 1000 and 500 mg/kg/day, respec vely.

Mutagenicity

Latanoprost

Latanoprost was found nega ve in reverse muta on tests in bacteria, gene muta on test in mouse lymphoma and mouse micronucleus test. Chromosome aberra ons were observed at cytotoxic concentra ons in vitro with human lymphocytes. Similar effects have been reported with prostaglandin F2α, a naturally occurring prostaglandin, which indicates that this is a class effect. Addi onal mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were nega ve and the conclusion is that latanoprost has no mutagenic poten al.

Timolol

Timolol was not mutagenic in vivo in the mouse micronucleus test and cytogene c assay, or in vitro in a neoplas c cell transforma on assay. In the Ames test, sta s cally significant increases in revertants were found at the highest concentra ons employed (5000 or 10000 mcg per plate) with tester strain TA 100, but not in the remaining three strains. However, the results of the in vitro microbial assay were not considered posi ve, because a ra o of the test to control revertants of 2 was never a ained.

Special Toxicology

Local Tolerance: No local irrita on or toxicity was observed a er twice daily topical applica on of latanoprost and molol ophthalmic solu on on the rabbit eye for 4 weeks or once daily applica on for 52 weeks.

1. 17.

   SUPPORTING PRODUCT MONOGRAPH

   1. 1. XALACOM® (ophthalmic solu on, latanoprost 50 mcg/mL and molol 5 mg/mL), submission control 277053, Product Monograph, BGP Pharma ULC. (JUL 21, 2023)