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XALACOM (latanoprost and timolol ophthalmic solution (as timolol maleate)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

ophthalmic

fixed combination of latanoprost 50 µg/mL and timolol 5 mg/mL as timolol maleate

XALACOM contains: benzalkonium chloride, For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

XALACOM (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 XALACOM (the combination drug) is considered appropriate.

XALACOM should not be used to initiate therapy.

For details of information obtained from Clinical Trials with XALACOM, please refer to CLINICAL TRIALS section.  Also see DOSAGE AND ADMINISTRATION.

Contraindications

XALACOM (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 latanoprost, timolol, benzalkonium chloride or any other ingredient in the product. For a complete listing, see the DOSAGE FORMS, COMPOSITION and PACKAGING section of the product monograph.

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 CONSUMER 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: XALACOM (latanoprost and timolol maleate) may interact with other drugs (see DRUG INTERACTIONS). The effect on intraocular pressure or the known effects of systemic beta-adrenergic blocking agents may be exaggerated when XALACOM 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 DOSAGE AND 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, XALACOM 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.

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

XALACOM 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 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 ADVERSE REACTIONS).

Due to the prostaglandin component latanoprost, XALACOM should be used with caution in patients with a history of herpetic keratitis. XALACOM 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 XALACOM. Contact lenses may be reinstalled 15 minutes after administering XALACOM.

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. XALACOM 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 XALACOM, 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: XALACOM 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

XALACOM has not been studied in patients with renal impairment and therefore should be used with caution in such patients.

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, XALACOM 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.

Sexual Function / Reproduction

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.

Special Populations

Pregnant Women: No reproduction toxicity studies have been conducted with XALACOM. 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 µg/kg/day IV and total litter resorption at > 50 µg/kg/day IV. No embryofetal effects were seen in rabbits at 1 µg/kg/day IV and in rats at up to 250 µg/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 µg/kg/day. At higher doses, increases in resorptions and fetal variations (14 ribs and hypoplastic sternebrae) were noticed in mice (1000 µg/kg/day) and increased resorption in rabbits (> 90 µg/kg/day). In rats, delayed ossification was seen ­> 50 µg/kg/day and a decreased number of caudal vertebral bodies and arches and an increase in hypoplastic sternebrae were noted at 500 µg/kg/day.

For additional information, see TOXICOLOGY.

XALACOM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women: 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 XALACOM in nursing infants, XALACOM should be used with caution in nursing women.

Pediatrics: XALACOM is not recommended for use in children. The safety and efficacy of the use of XALACOM in children has not been established.

Adverse Reactions

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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

XALACOM 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 XALACOM 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 1 and 2.

Table 1
Ocular adverse events (AE) that occurred in ≥ 1% of patients*, in any treatment group, by preferred term†
*
Despite a low frequency of reports, some AEs are included in the listing due to the implication of a potentially sight-threatening condition.
**
A patient is counted only once per preferred term
Studies 004 and 005 included a 6 month and 053 a 12 month double-blinded period
Include*s darkening, lengthening and growing of eye lashes
 

Number (%) of patients per treatment group

Body system / preferred term

Xalacom

N=394

Latanoprost

N=414

Timolol

N=415

Vision

Blepharitis

10 (2.5)

10 (2.4)

7 (1.7)

Cataract

11 (2.8)

18 (4.3)

10 (2.4)

Conjunctival disorder

4 (1.0)

3 (0.7)

4 (1.0)

Conjunctivitis

12 (3.0)

11 (2.7)

13 (3.1)

Corneal disorder

12 (3.0)

11 (2.7)

14 (3.4)

Corneal ulceration

1 (0.3)*

1 (0.2)*

-

Cystoid macular oedema

1 (0.3)**

1 (0.2)*

-

Epiphora

3 (0.8)

5 (1.2)

7 (1.7)

Errors of refraction

7 (1.8)

13 (3.1)

12 (2.9)

Eye hyperaemia

29 (7.4)

40 (9.7)

12 (2.9)

Eye pain

9 (2.3)

6 (1.4)

8 (1.9)

Increased intraocular pressure

1 (0.3)

5 (1.2)

7 (1.7)

Iris hyperpigmentation

6 (1.5)

13 (3.1)

4 (1.0)

Iritis

-

1 (0.2)*

2 (0.5)*

Irritation eye (burning, grittiness, itching, stinging and foreign body sensation)

49 (12.4)

54 (13.0)

29 (7.0)

Keratitis

4 (1.0)

3 (0.7)

1 (0.2)

Oedema eyelid

2 (0.5)

4 (1.0)

2 (0.5)

Photophobia

6 (1.5)

1 (0.2)

3 (0.7)

Retinal disorder

1 (0.3)

3 (0.7)

6 (1.4)

Uveitis

1 (0.3)*

-

-

Vision abnormal

26 (6.6)

29 (7.0)

22 (5.3)

Skin & Appendages

Hypertrichosis‡

9 (2.3)

6 (1.4)

2 (0.5)

Pigmentation abnormal

1 (0.3)*

-

-

Seborrhoea

2 (0.5)

4 (1.0)

-

Skin discolouration

1 (0.3)*

-

-

Skin disorder

8 (2.0)

4 (1.0)

-

Central & Peripheral Nervous System

Optic atrophy

2 (0.5)

3 (0.7)

6 (1.4)

Visual field defect

18 (4.6)

19 (4.6)

18 (4.3)

Table 2:
Systemic adverse events (AE) that occurred in ≥1% of patients*, in any of the treatment groups, by body system/preferred term†
*
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.
Studies 004 and 005 included a 6 month- and 053 a 12 month double-blinded period
 

Number (%) of patients per treatment group

Body system / preferred term

Xalacom

N=394

Latanoprost

N=414

Timolol

N=415

Respiratory

Bronchitis

3 (0.8)

4 (1.0)

1 (0.2)

Coughing

1 (0.3)*

-

2 (0.5)*

Dyspnoea

2 (0.5)*

2 (0.5)*

2 (0.5)*

Pneumonia

1 (0.3)

3 (0.7)

4 (1.0)

Sinusitis

6 (1.5)

11 (2.7)

3 (0.7)

Upper respiratory tract infection

24 (6.1)

18 (4.3)

22 (5.3)

General

Back pain

4 (1.0)

6 (1.4)

4 (1.0)

Chest pain

4 (1.0)

1 (0.2)

2 (0.5)

Influenza-like symptoms

10 (2.5)

4 (1.0)

3 (0.7)

Cardiovascular

Hypertension

15 (3.8)

6 (1.4)

10 (2.4)

Hypertension aggravated

2 (0.5)*

1 (0.2)*

1 (0.2)*

Metabolic & Nutrition

Diabetes mellitus

5 (1.3)

2 (0.5)

1 (0.2)

Diabetes mellitus aggravated

-

1 (0.2)

-

Glycosuria

2 (0.5)

1 (0.2)

-

Hyperglycaemia

1 (0.3)*

2 (0.5)*

2 (0.5)*

Hypercholesterolaemia

6 (1.5)

4 (1.0)

1 (0.2)

Central & Peripheral Nervous System

Dizziness

2 (0.5)

4 (1.0)

1 (0.2)

Headache

9 (2.3)

15 (3.6)

5 (1.2)

Musculo-Skeletal

Arthritis

8 (2.0)

5 (1.2)

4 (1.0)

Psychiatric

Depression

6 (1.5)

7 (1.7)

4 (1.0)

Insomnia

1 (0.3)*

1 (0.2)*

1 (0.2)*

Sleep disorder

1 (0.3)

-

4 (1.0)

Skin & Appendages

Bullous eruption

-

1 (0.2)

-

Rash

5 (1.3)

3 (0.7)

2 (0.5)

Resistance Mechanisms

Infection

4 (1.0)

6 (1.4)

(1.4)

Gastro-Intestinal

Dyspepsia

2 (0.5)

4 (1.0)

1 (0.2)

Urinary

Cystitis

1 (0.3)

5 (1.2)

-

Urinary tract infection

1 (0.3)

2 (0.5)

4 (1.0)

Based on evidence from consecutive photographs, increased iris pigmentation was observed in 16-20% of patients treated with XALACOM 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.

Post-Market Adverse Drug Reactions

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

Latanoprost

System Organ Class

Adverse Drug Reactions

Cardiac disorders

Angina unstable, angina, palpitations

Eye disorders

Foreign body sensation, macular oedema including cystoid macular oedema, corneal erosion, punctate keratitis, corneal oedema, uveitis, iritis, pseudopemphigoid of ocular conjunctiva, trichiasis, photophobia, vision blurred, eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and number of eyelashes), localised skin reaction on the eyelids, iris cyst, periorbital and lid changes resulting in deepening of the eyelid sulcus, darkening of the palpebral skin of the eyelids

General disorders and administration site conditions

Chest pain

Infections and infestations

Herpetic keratitis

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia

Nervous system disorders

Dizziness

Respiratory, thoracic and mediastinal disorders

Acute asthma attacks, asthma aggravation, asthma, dyspnoea

Skin and subcutaneous tissue disorders

Pruritus

Timolol Maleate (topical formulation)

System Organ Class

Adverse Drug Reactions

Cardiac disorders

Cardiac arrest, cardiac failure, heart block, atrioventricular block, congestive heart failure, worsening of angina pectoris, arrhythmia, bradycardia, palpitation

Ear and labyrinth disorders

Tinnitus

Eye disorders

Cystoid macular oedema, choroidal detachment (following filtration surgery), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, signs and symptoms of ocular irritation (e.g., burning, stinging, itching, tearing, redness), dry eyes, ptosis, blepharitis, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), vision blurred

Gastrointestinal disorders

Retroperitoneal fibrosis, abdominal pain, vomiting, diarrhoea, dry mouth, dysgeusia, dyspepsia, nausea

General disorders and administration site conditions

Chest pain, oedema, asthenia, fatigue

Immune system disorders

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

Metabolism and nutrition disorders

Masked symptoms of hypoglycaemia in diabetic patients, anorexia

Musculoskeletal and connective tissue disorders

Myalgia, systemic lupus erythematosus

Nervous system disorders

Cerebral vascular accident, cerebral ischemia, dizziness, increase in signs and symptoms of myasthenia gravis, paraesthesia, somnolence, headache, syncope

Psychiatric disorders

Behavioural changes and psychic disturbances including, confusion, hallucinations, anxiety, disorientation, nervousness, depression, insomnia, nightmares, memory loss

Reproductive system and breast disorders

Sexual dysfunction, decreased libido, impotence, Peyronie’s disease

Respiratory, thoracic and mediastinal disorders

Respiratory failure, pulmonary oedema, bronchospasm (predominantly in patients with pre-existing bronchospastic disease), cough, dyspnoea, nasal congestion

Skin and subcutaneous tissue disorders

Skin rash, psoriasiform rash, pseudopemphigoid, exacerbation of psoriasis, alopecia

Vascular disorders

Claudication, cold hands and feet, hypotension, Raynaud’s phenomenon

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.

Drug Interactions

Drug-Drug Interactions

No specific interaction studies have been performed with XALACOM (latanoprost and timolol maleate).

Patients who are receiving treatment with XALACOM 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, guanethidineand 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 XALACOM 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 XALACOM. 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 Drug-Lifestyle Interactions: Use of Contact Lenses).

Drug-Lifestyle Interactions

Effects on ability to drive and use of machines: In common with other eye preparations, installation of eye drops may cause transient blurring of vision.

Use of Contact Lenses: XALACOM 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 Drug-Drug Interactions) Therefore, contact lenses should be removed before installation of the eye drops and may be reinserted after 15 minutes.

Dosage And Administration

The recommended adult (including the elderly) dosage of XALACOM (latanoprost and timolol maleate) is one drop in the affected eye(s) once daily.  If one dose is missed, treatment should continue with the next dose as normal. 

The use of XALACOM 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 XALACOM once daily.  The IOP lowering effect of XALACOM 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 CLINICAL TRIALS section.

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.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There is no human data available on overdosage with XALACOM (latanoprost and timolol maleate).

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 µg/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 µg/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.

In monkeys latanoprost has been infused intravenously to doses up to 500 µg/kg without major effects on the cardiovascular system.  Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction.

If overdose with XALACOM occurs, treatment should be symptomatic.

If XALACOM is accidentally ingested the following information may be useful: One bottle contains 125 µg 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.

Action And Clinical Pharmacology

Mechanism of Action

XALACOM (latanoprost and timolol maleate) consists of two components: latanoprost and timolol maleate. Each mL of XALACOM 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 XALACOM once daily results in additional intraocular pressure reduction compared to either component administered alone separately. For details of information obtained from Clinical Trials with XALACOM, please refer to CLINICAL TRIALS section.

Pharmacokinetics

Latanoprost: 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 in man indicate that the maximum concentration in the aqueous humor, approximately 30 ng/mL, is reached about 2 hours after topical administration of latanoprost alone. The acid of latanoprost has a plasma clearance of 0.40 L/h/kg and a small volume of distribution, 0.16 L/kg, resulting in a rapid half-life in plasma (17 minutes). 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%. 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 in animal studies and are excreted primarily in the urine.

Timolol: 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 µg/day). The half-life of timolol in plasma is about 6 hours. Timolol is extensively metabolized in the liver. The metabolites, and unchanged timolol, are excreted in the urine.

XALACOM: 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

Elderly, Gender, Pediatric and Race: Differences in the pharmacokinetics of XALACOM in these populations has not been investigated.

Diseases and Demographic Characteristics: No studies have been performed to investigate the influence of other diseases or demographic characteristics on the pharmacokinetics of XALACOM due to the inherit difficulties in measuring the drug concentrations after topical administration on the eyes.

Storage And Stability

Store unopened bottle under refrigeration (2°C to 8°C).  Protect from light.  Once opened, the 2.5 mL container may be stored at room temperature up to 25ºC for 10 weeks.  Protect from light.

Dosage Forms, Composition And Packaging

XALACOM (latanoprost and timolol maleate) is a sterile, isotonic, buffered, clear and colorless aqueous solution. One drop contains approximately 1.5 µg of latanoprost and 150 µg of timolol.

XALACOM is intended for topical administration on the eye.

XALACOM 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 XALACOM corresponding to approximately 80 drops of solution.

XALACOM 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 (µg) 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.

 

Control #: 207642
7 September 2017

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