Mylan-Latanoprost/Timolol (Mylan Pharmaceuticals, 50 mcg / 5 mg) Product Monograph

RECENT MAJOR LABEL CHANGES

None at the time of most recent authorization

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

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

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

1 INDICATIONS ............................................................................................................. 4

1.1 Pediatrics .................................................................................................................. 4

1.2 Geriatrics .................................................................................................................. 4

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

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

5 OVERDOSAGE ............................................................................................................ 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................ 6

7 WARNINGS AND PRECAUTIONS ................................................................................. 6

7.1 Special Populations ................................................................................................ 10

7.1.1 Pregnant Women ............................................................................................. 10

7.1.2 Breast-feeding .................................................................................................. 10

7.1.3 Pediatrics .......................................................................................................... 10

8 ADVERSE REACTIONS............................................................................................... 11

8.1 Adverse Reaction Overview ................................................................................... 11

8.2 Clinical Trial Adverse Reactions ............................................................................. 11

8.5 Post-Market Adverse Reactions ............................................................................. 15

9 DRUG INTERACTIONS .............................................................................................. 16

9.2 Drug Interaction Overview ..................................................................................... 16

9.4 Drug-Drug Interactions .......................................................................................... 17

9.5 Drug-Food Interactions .......................................................................................... 18

9.6 Drug-Herb Interactions .......................................................................................... 18

9.7 Drug-Laboratory Test Interactions......................................................................... 18

10 CLINICAL PHARMACOLOGY ...................................................................................... 18

10.1 Mechanism of Action ....................................................................................... 18

10.3 Pharmacokinetics ............................................................................................. 19

11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 20

12 SPECIAL HANDLING INSTRUCTIONS .......................................................................... 21

PART II: SCIENTIFIC INFORMATION ..................................................................................... 22

13 PHARMACEUTICAL INFORMATION .......................................................................... 22

14 CLINICAL TRIALS ...................................................................................................... 23

14.1 Clinical Trials by Indication .............................................................................. 23

15 MICROBIOLOGY ...................................................................................................... 25

16 NON-CLINICAL TOXICOLOGY .................................................................................... 26

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................... 29

PATIENT MEDICATION INFORMATION ................................................................................ 30

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

MYLAN-LATANOPROST/TIMOLOL (latanoprost and timolol maleate) is indicated for the reduction of intraocular pressure (IOP) in patients 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 MYLAN-LATANOPROST/TIMOLOL (the combination 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 indication for pediatric use (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics: Based on the data submitted and reviewed by Health Canada, there is no overall difference in the safety and efficacy of MYLAN-LATANOPROST/TIMOLOL use in the geriatric patient population.

2 CONTRAINDICATIONS

Latanoprost and timolol maleate is contraindicated in patients with:

• reactive airway disease including bronchial asthma, a history of bronchial asthma, or severe chronic obstructive 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 hypersensitivity 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 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• The use of MYLAN-LATANOPROST/TIMOLOL may be considered in patients who require both timolol and latanoprost. It has not been fully investigated whether patients who are adequately controlled with timolol twice daily plus latanoprost once daily will be effectively controlled with MYLAN-LATANOPROST/TIMOLOL once daily. The IOP lowering effect of MYLAN-LATANOPROST/TIMOLOL once daily may be less than that seen with the concomitant administration of timolol twice daily and latanoprost once daily based on the results from a short term clinical trial. For details of information obtained from the clinical trial, please refer to the 14 CLINICAL TRIALS section.
• MYLAN-LATANOPROST/TIMOLOL contains benzalkonium chloride which may be absorbed by contact lenses. Several contact lens soaking solutions contain thimerosal which may also form a precipitate with benzalkonium chloride (see 9.4 Drug-Drug Interactions) Therefore, contact lenses should be removed before installation of the eye drops and may be reinserted after 15 minutes.
• MYLAN-LATANOPROST/TIMOLOL should not be used to initiate therapy

4.2 Recommended Dose and Dosage Adjustment

The recommended adult (including the elderly) dosage of MYLAN-LATANOPROST/TIMOLOL is one drop in the affected eye(s) once daily.

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

4.4 Administration

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

4.5 Missed Dose

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

5 OVERDOSAGE

There is no human data available on overdosage with MYLAN-LATANOPROST/TIMOLOL.

Symptoms of systemic timolol overdosage are: bradycardia, hypotension, bronchospasm, and cardiac arrest. If such symptoms occur, treatment should be symptomatic and supportive. Studies have shown that timolol is not readily dialyzable.

Apart from ocular irritation and conjunctival 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, fatigue, hot flashes, and sweating. These events were mild to moderate in severity and resolved without treatment within 4 hours after terminating the infusion.

If overdose with MYLAN-LATANOPROST/TIMOLOL occurs, treatment should be symptomatic.

If MYLAN-LATANOPROST/TIMOLOL is accidentally ingested the following information may be useful: One bottle contains 125 mcg latanoprost and 12.5 mg timolol. Both timolol 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, Composition and Packaging

MYLAN-LATANOPROST/TIMOLOL is a sterile, isotonic, buffered, clear and colorless aqueous solution. One drop contains approximately 1.5 mcg of latanoprost and 150 mcg of timolol. MYLAN-LATANOPROST/TIMOLOL is intended for topical administration on the eye.

MYLAN-LATANOPROST/TIMOLOL is supplied in a 5 mL plastic ophthalmic dispenser bottle with a dropper tip, screw cap and tamper proof polyethylene overcap.

Each bottle contains 2.5 mL of MYLAN-LATANOPROST/TIMOLOL corresponding to approximately 80 drops of solution.

MYLAN-LATANOPROST/TIMOLOL is supplied as a sterile, isotonic, buffered, clear and colorless aqueous solution 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 timolol (6.83 mg timolol maleate).

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

7 WARNINGS AND PRECAUTIONS

General

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption 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 patients and pigmentary glaucoma.

Concomitant therapy: MYLAN-LATANOPROST/TIMOLOL may interact with other drugs (see 9.4 Drug-Drug Interactions). The effect on intraocular pressure or the known effects of systemic beta-adrenergic blocking agents may be exaggerated when MYLAN-LATANOPROST/TIMOLOL is given to patients 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 elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

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

Incidence of systemic adverse drug reactions after topical ophthalmic administration is lower than for systemic administration. The systemic absorption can be reduced by using nasolacrimal occlusion or closing the eyelids for 2 minutes (see 4.4 Administration).

Cardiovascular

Cardiac reactions: Death associated with cardiac failure has been reported. Cardiac failure should be adequately controlled before beginning treatment. Patients 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, MYLAN-LATANOPROST/TIMOLOL should be discontinued. Due to its negative effect on conduction time, beta-adrenergic blocking agents should only be given with caution to patients with first degree heart block.

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

Driving and Operating Machinery

In common with other eye preparations, installation of eye drops may cause transient blurring of vision.

Endocrine and Metabolism

Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with caution in patients subjected to spontaneous hypoglycemia or to 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.

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.

Hepatic/Biliary/Pancreatic

MYLAN-LATANOPROST/TIMOLOL has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Neurologic

Muscle Weakness: Beta-adrenergic blocking agents have been reported to rarely increase muscle weakness in some patients 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 Reactions).

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

Due to the prostaglandin component latanoprost, MYLAN-LATANOPROST/TIMOLOL should be used with caution in patients with a history of herpetic keratitis. MYLAN-LATANOPROST/TIMOLOL should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

This product contains benzalkonium chloride as a preservative, which may be absorbed by soft contact lenses. Remove contact lenses before administration of MYLAN-LATANOPROST/TIMOLOL. Contact lenses may be reinstalled 15 minutes after administering MYLAN-LATANOPROST/TIMOLOL.

Ophthalmic beta-adrenergic blocking agents may induce dryness of eyes. These agents should be used prescribed with caution in patients with corneal diseases.

Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost ophthalmic solution. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. MYLAN-LATANOPROST/TIMOLOL should be used with caution in these patients.

Choroidal detachment after filtration procedures has been reported with the administration of ocular hypotensive agents.

Changes to Pigmented Tissues: Latanoprost, the prostaglandin component contained in MYLAN-LATANOPROST/TIMOLOL, 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 pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. The change in iris colour occurs slowly and may not be noticeable for several months to years. The long term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye is currently unknown. Patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues.

This effect has predominantly been seen in patients with mixed colored irides (i.e. blue/gray-brown, green-brown, or yellow-brown). In patients 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 noticeable for several months to years. Patients should be informed of the possibility of iris color change. Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation in the treated eye and thus, permanent heterochromia between the eyes. The increased pigmentation is permanent.

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

Closed Angle Glaucoma: MYLAN-LATANOPROST/TIMOLOL should not be used alone in the treatment of acute closed angle glaucoma. In patients with closed angle glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Latanoprost and Timolol Maleate have little or no effect on the pupil.

Peri-Operative Considerations

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 stimuli, which may augment the risk of general anesthesia in surgical procedures. Protracted severe hypotension during anesthesia and difficulty restarting 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 preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

Renal

MYLAN-LATANOPROST/TIMOLOL has not been studied in patients with renal impairment and therefore should be used with caution in such patients.

Reproductive Health: Female and Male Potential

• Fertility

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

Respiratory

Respiratory Reactions: Severe respiratory reactions including death due to bronchospasm in patients with asthma and rarely death associated with cardiac failure have been reported following administration of beta-adrenergic blocking agents.

Respiratory Disorders: Due to the beta-adrenergic component timolol maleate, MYLAN-LATANOPROST/TIMOLOL should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

Sensitivity/Resistance

Anaphylactic Reactions: While taking beta-adrenergic blocking agents, patients with a history of atopy or severe anaphylactic reaction to a variety of allergens may be more sensitive to repeated challenge. These could include environmental, diagnostic or therapeutic allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

7.1 Special Populations

7.1.1 Pregnant Women

No reproduction toxicity studies have been conducted with MYLAN-LATANOPROST/TIMOLOL. 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 resorption and reduced fetal weight at 5 mcg/kg/day IV and total litter resorption 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 timolol 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 resorptions and fetal variations (14 ribs and hypoplastic sternebrae) were noticed in mice (1000 mcg/kg/day) and increased resorption in rabbits (≥ 90 mcg/kg/day). In rats, delayed ossification was seen ≥ 50 mcg/kg/day and a decreased number of caudal vertebral bodies and arches and an increase in hypoplastic sternebrae were noted at 500 mcg/kg/day.

For additional information, see 16 NON-CLINICAL TOXICOLOGY.

MYLAN-LATANOPROST/TIMOLOL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

7.1.2 Breast-feeding

There are limited experimental animal and no human data available on the pharmacokinetics of latanoprost lactation. Latanoprost and its metabolites may pass into breast milk. Timolol maleate has been detected in human milk following oral and ocular administration. Because of the potential for serious adverse reactions from MYLAN-LATANOPROST/TIMOLOL in nursing infants, MYLAN-LATANOPROST/TIMOLOL should be used with caution in nursing women.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of the use of MYLAN-LATANOPROST/TIMOLOL in children has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most commonly reported ocular adverse reactions in controlled clinical trials, that may be associated with combination therapy of latanoprost and timolol maleate were eye irritation (12.4 %), eye hyperaemia (7.4 %), abnormal vision (6.6 %), conjunctivitis (3.0 %) and corneal disorder (3.0 %) (see 8.2 Clinical Trial Adverse Reactions). The most commonly reported systemic adverse reactions in controlled clinical trials, that may be associated with combination therapy of latanoprost and timolol maleate were upper respiratory track infection (6.1 %), hypertension (3.8 %), influenza-like symptoms (2.5 %) and headache (2.3 %) (see 8.2 Clinical Trial Adverse Reactions).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Combination therapy of latanoprost and timolol maleate was generally well tolerated. No adverse events specific to the combination therapy of latanoprost and timolol maleate have been observed in clinical studies. The adverse events have been limited to those that were reported previously with latanoprost and/or timolol maleate.

Combination therapy of latanoprost and timolol maleate was evaluated for safety in 394 patients with open-angle glaucoma or ocular hypertension in three long-term studies. Two percent (2%) of patients discontinued therapy with combination therapy of latanoprost and timolol maleate due to adverse events.

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

Table 2. Ocular adverse events (AE) that occurred in ≥ 1% of patients*, in any treatment group, by preferred term†

Table 3. Systemic adverse events (AE) that occurred in ≥1% of patients*, in any of the treatment groups, by body system/preferred term†

Based on evidence from consecutive photographs, increased iris pigmentation was observed in 16-20% of patients treated with latanoprost and timolol maleate combination therapy for up to one year. The most frequent findings of increased iris pigmentation were in the known high-risk eye color groups, i.e. those with green-brown, yellow-brown, and blue/gray-brown irises. In patients 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 patients.

8.5 Post-Market Adverse Reactions

The following additional adverse events that have been reported with latanoprost and timolol eye drops:

Latanoprost

Timolol Maleate (topical formulation)

Cases of corneal calcification have been reported very rarely in association with the use of phosphate-containing eye drops in some patients with significantly damaged corneas.

9 DRUG INTERACTIONS

9.2 Drug Interaction Overview

No specific interaction studies have been performed with MYLAN-LATANOPROST/TIMOLOL.

Patients who are receiving treatment with MYLAN-LATANOPROST/TIMOLOL and an oral beta-adrenergic blocking agent should be observed for potential additive 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 elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

The potential exists for additive effects resulting in hypotension, and/or marked bradycardia when timolol ophthalmic drops are administered with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrythmics (including amiodarone and quinidine), digitalis glycosides, parasympathomimetics, narcotics, guanethidine and monoamine oxidase (MAO) inhibitors.

Potentiated systemic beta adrenergic blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

Although MYLAN-LATANOPROST/TIMOLOL alone has little or no effect on pupil size, mydriasis has occasionally been reported when timolol is given with epinephrine.

Beta-adrenergic blocking agents may increase the hypoglycemic effect of antidiabetic agents.

In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with benzalkonium chloride, the preservative used in MYLAN-LATANOPROST/TIMOLOL. If such drugs are used they should be administered with an interval of at least 5 minutes between applications. Similarly, several contact lens soaking solutions contain thimerosal (see 4.4 Administration).

9.4 Drug-Drug Interactions

Table 4 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

MYLAN-LATANOPROST/TIMOLOL consists of two components: latanoprost and timolol maleate. Each mL of MYLAN-LATANOPROST/TIMOLOL contains latanoprost 50 micrograms and timolol maleate 6.8 mg equivalent to 5 mg timolol. These two components decrease elevated intraocular pressure (IOP) by different mechanisms of action.

Latanoprost is a prostanoid selective FP receptor agonist which reduces the IOP by increasing the outflow of aqueous humor. The main mechanism of action is increased uveoscleral outflow. In addition, some increase in outflow facility (decrease in trabecular outflow resistance) has been reported in man. Timolol maleate is a beta₁ and beta₂ (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol lowers the IOP by decreasing the formation of aqueous humor in the ciliary epithelium. The precise mechanism of action is not clearly established. The combined effect of these two agents administered as MYLAN-LATANOPROST/TIMOLOL once daily results in additional intraocular pressure reduction compared to either component administered alone separately. For details of information obtained from Clinical Trials with latanoprost and timolol maleate combination therapy, please refer to 14 CLINICAL TRIALS section.

10.3 Pharmacokinetics

Table 5 - Summary of latanoprost Pharmacokinetic Parameters in aqueous humor in adults

Table 6 - Summary of latanoprost Pharmacokinetic Parameters in plasma in adults

Table 7 - Summary of timolol Pharmacokinetic Parameters in aqueous humor in adults

Table 8 - Summary of timolol Pharmacokinetic Parameters in plasma in adults

Latanoprost

Absorption: Latanoprost is an isopropyl ester prodrug which is inactive but becomes biologically active after 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 concentration in the aqueous humor, approximately 30 ng/mL, is reached about 2 hours after topical administration of latanoprost alone. After topical ocular administration, the systemic bioavailability of the acid of latanoprost is 45%. The acid of latanoprost has a plasma protein binding of 87%.

Distribution: The acid of latanoprost has a small volume of distribution of 0.16 L/kg.

Metabolism: Latanoprost is an isopropyl ester prodrug which is inactive but becomes biologically active after hydrolysis to the acid of latanoprost. The main metabolism occurs in the liver. There is practically 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 activity

Elimination: 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 activity in animal studies and are excreted primarily in the urine.

Timolol

Absorption: The maximum concentration of timolol in the aqueous humor is reached about one hour after topical ocular administration. Part of the dose is absorbed systemically and a maximum plasma concentration of 1 ng/mL is reached 10-20 minutes after topical ocular administration of one drop to each eye once daily (300 mcg/day).

Metabolism: Timolol is extensively metabolized in the liver.

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

Latanoprost and Timolol maleate

No pharmacokinetic interactions between latanoprost and timolol have been observed although the aqueous humor concentrations of the acid of latanoprost tended to be higher 1 to 4 hours after administration of the combination product compared to monotherapy with either latanoprost or timolol.

Special Populations and Conditions

Pediatrics: Differences in the pharmacokinetics of latanoprost and timolol maleate combination therapy in this population has not been investigated.

Geriatrics: Differences in the pharmacokinetics of latanoprost and timolol maleate combination therapy in this population has not been investigated.

Sex: Differences in the pharmacokinetics of latanoprost and timolol maleate combination therapy in this population has not been investigated.

Ethnic Origin: Differences in the pharmacokinetics of latanoprost and timolol maleate combination therapy in this population has not been investigated.

Hepatic Insufficiency: No studies have been performed to investigate the influence of demographic characteristics on the pharmacokinetics of latanoprost and timolol maleate combination therapy due to the inherent difficulties in measuring the drug concentrations after topical administration on the eyes.

Renal Insufficiency: No studies have been performed to investigate the influence of demographic characteristics on the pharmacokinetics of latanoprost and timolol maleate combination therapy due to the inherent difficulties in measuring the drug concentrations after topical administration on the eyes.

11 STORAGE, STABILITY AND DISPOSAL

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

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions for this drug product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

MYLAN-LATANOPROST/TIMOLOL contains latanoprost and timolol 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) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF₂ α-isopropyl ester

Molecular formula and molecular Mass: C₂₆H₄₀O₅ and 432.58

Structural Formula:

Physicochemical Properties:

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 practically insoluble in water.

Timolol Maleate:

Proper Name: timolol maleate

Chemical Name: S)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt)

Molecular formula and molecular mass: C₁₃H₂₄N₄O₃S•C₄H₄O₄ and 432.50

Structural Formula:

Physicochemical Properties:

Physical form White to off-white crystalline powder

Solubility Soluble in water, alcohol and practically insoluble in ether.

pH 3.8 - 4.3 (2% in Water)

pKa 9.2

Melting Point 200 - 202ºC with decomposition

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Reduction of intraocular pressure (IOP) in patients 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, multicenter clinical studies were conducted to compare the IOP-lowering effect of latanoprost and timolol maleate combination therapy dosed once daily to latanoprost 50 mcg/mL dosed once daily and timolol 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%), exfoliative glaucoma (4%) and other (2%). Patients enrolled could have been on previous therapy (88%) or not on medication (12%) and were required to have an IOP of ≥ 25 mmHg if on medication or ≥30 mmHg if not on therapy at enrollment. There was no restriction on the number or type of glaucoma medications taken prior to study entry. The distribution of patients at enrollment on glaucoma medication and not on glaucoma medication were similar in each of the three treatment groups. Approximately 70% of patients were on timolol therapy prior to enrollment. In the studies the baseline study visit was preceded by a 2-4 weeks run-in period on timolol 5 mg/mL bid.

Table 10 and 11 shows the mean diurnal IOP reductions at the end of the treatment latanoprost and timolol maleate fixed combination (FC) and the individual monotherapies for all patients. All values are statistically significant.

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

Patients enrolled could have been on previous therapy (88%) or not on medication (12%). Analysis on the primary efficacy endpoints for studies 004 and 005 indicate that inclusion or exclusion of patients who are not on medication prior to enrollment (12%) had no influence on statistical outcome of efficacy observed in the studies.

In clinical practice, the appropriate value of a target IOP (an IOP level that would be considered a clinical success) is determined by the physician for each patient. Information from the recent Advanced Glaucoma Intervention 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 timolol maleate combination therapy over the individual monotherapies as shown in Table 12.

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

A short term double blind, controlled, crossover study (n=190) was performed to evaluate latanoprost and timolol maleate fixed combination (FC) versus the individual monotherapies (latanoprost once daily and timolol 5 mg/mL twice daily administered separately, uFC) in maintaining the IOP of well-controlled patients on the combination of the individual monotherapies. In this study patients 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 respectively. Results from this short-term crossover study indicates that latanoprost and timolol maleate combination therapy maintained the IOP seen in the population at enrollment while the concomitant use of the individual monotherapies resulted in a decrease in the IOP. Overall, the mean IOP after 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 after six weeks of dosing was 0.8 to 1.4 mmHg.

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

There are no data to show the optimal dose of latanoprost and timolol in combination.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity

Latanoprost and timolol maleate

A single subcutaneous dose of 20 mL/kg, corresponding to 1 mg/kg of latanoprost and 100 mg/kg of timolol, was well tolerated in rats and the only finding was a local reaction at the site of injection (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 after oral administration was 1190 mg/kg in mice and 900 mg/kg in rats. The corresponding values after parenteral administration were 225 mg/kg (i.v.) and 383 mg/kg (i.p.), respectively. Infant rats were more sensitive 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, respectively.

Repeated Dose Toxicity

Latanoprost and timolol maleate

Local toxicity has been investigated after twice daily topical application in pigmented rabbits for 4 weeks. The daily dose of latanoprost was 3 mcg/eye and that of timolol was 300 mcg/eye. No local ocular irritation or changes at ophthalmological examinations were found and there were no macroscopic and microscopic alterations.

Chronic local and systemic toxicity has also been evaluated in pigmented rabbits. One drop once daily ocular administration, corresponding to 1.5 mcg/eye/day of latanoprost and 150 mcg/eye/day of timolol, produced no evidence of local irritation, and ocular or systemic toxicity, as assessed by ophthalmoscopy, tonometry, pachymetry, clinical chemistry, and complete gross and microscopic examinations. In conclusion, the application of latanoprost and timolol ophthalmic solution to the rabbit eye for 52 weeks was well tolerated.

Latanoprost

Ocular and systemic toxicity of latanoprost has been investigated 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 hypersalivation and miosis during infusion followed by vomiting and sometimes 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 pigmentation 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 supportive tissue 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 pigmentation

The increased iridial pigmentation 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 particular interest that naturally occurring prostaglandins such as PGF_2α and PGE₂ also cause increased pigmentation 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 selective 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 tissues of the eye.

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

In a 104-week ocular toxicity study in rhesus monkeys, the iridial stroma exhibited a more intense pigmentation of the pigmented cells in all treated groups, but remained morphologically normal at the end of the treatment and recovery periods. A quantitative morphometric analysis showed an increase in the number of melanosomes in iridial melanocytes, and an increase in the cell area and ratio 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 modification in melanosome number and size with treatment and an apparent tendency towards reversibility after an extensive recovery period.

Morphological examination of three iridectomy specimens from patients indicated that the eye color change after long-term topical treatment with latanoprost is more likely produced by increased melanin density per melanocyte, or movement and rearrangement of cells in the tissue than by proliferation of melanocytes. Thus, there are no indications of any toxic effects of latanoprost on the pigment containing cells of the iris. In addition, results have shown that the increase of pigmentation is due to increased synthesis or turnover of melanin in the iridial melanocytes, and no proliferative changes occur during pigmentation.

Timolol

In rats, oral administration of timolol for 8 weeks was associated with increased spleen weights and splenic congestion 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 after 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 after repeated administration 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 multiple daily topical doses up to 6 mg/eye/day for 52 weeks or in dogs after three times daily instillation at doses up to 1.5 mg/eye/day, five days a week, for 104 weeks.

Carcinogenicity

Latanoprost

No carcinogenic potential was indicated in rodents after oral doses of up to 200 mcg/kg/day. At this dose, the maximum plasma concentrations of acid of latanoprost in mice and rats were at least 50 and 13 times higher, respectively, than those in humans after 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 times the exposure in humans after a maximum recommended ophthalmic dose of timolol. 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 elevation in serum prolactin.

Reproductive and Developmental Toxicology

Latanoprost

Latanoprost has no effects on fertility and general reproductive performance in male and female rats, and no teratogenic potential in rats or rabbits. No embryotoxicity was observed in rats after intravenous doses of up to 250 mcg/kg/day. However, latanoprost caused embryofetal toxicity, characterized by an increased incidence of late resorption and abortion, 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 attributed to a marked luteolytic effect in rabbits, a class effect of prostaglandin F_2α and its analogues. However, this effect is minimal in humans.

Timolol

Reproduction and fertility studies in rats showed no adverse effects on male or female fertility at oral doses of 300 and 450 mg/kg/day, respectively. No teratogenic effects or embryofetal toxicity was observed in mice, rats or rabbits after oral doses up to 50 mg/kg/day (about 7000 times the systemic exposure in humans after a maximum therapeutic dose of timolol ophthalmic solution). 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, respectively.

Mutagenicity

Latanoprost

Latanoprost was found negative in reverse mutation tests in bacteria, gene mutation test in mouse lymphoma and mouse micronucleus test. Chromosome aberrations were observed at cytotoxic concentrations in vitro with human lymphocytes. Similar effects have been reported with prostaglandin F_2α, a naturally occurring prostaglandin, which indicates that this is a class effect. Additional mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats were negative and the conclusion is that latanoprost has no mutagenic potential.

Timolol

Timolol was not mutagenic in vivo in the mouse micronucleus test and cytogenetic assay, or in vitro in a neoplastic cell transformation assay. In the Ames test, statistically significant increases in revertants were found at the highest concentrations 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 positive, because a ratio of the test to control revertants of 2 was never attained.

Special Toxicology

Local Tolerance: No local irritation or toxicity was observed after twice daily topical application of latanoprost and timolol ophthalmic solution on the rabbit eye for 4 weeks or once daily application for 52 weeks.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. XALACOM solution, 50 mcg / mL and 5 mg / mL, submission control 277053, Product Monograph, BGP Pharma ULC, JUL 21, 2023