9 PM Eye Drops (Latanoprost 0.005%)

Table of Content

Composition

Each ml contains:
Latanoprost ......................................... 50 mcg
Benzalkonium Chloride, NF ............. 0.02%w/v
(as preservative)
aqueous vehicle ................................... q.s.

Dosage Form

Ophthalmic solution

Description

Latanoprost is a prostaglandin F2 (alpha) analogue. Latanoprost is a prostanoid selective FP receptor agonist, which is believed to reduce the intraocular pressure by increasing the outflow of the aqueous humour. Studies in animals and humans suggest that the main mechanism of action is increased uveoscleral outflow.

Pharmacology

Pharmacodynamics

Mechanism of Action
Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of the aqueous humour. Studies in animals and humans suggest that the main mechanism of action is increased uveoscleral outflow. Elevated intraocular pressure represents a major risk factor for glaucomatous field loss. The higher the level of intraocular pressure, the greater the likelihood of optic nerve damage and visual field loss.

Pharmacokinetics

Absorption
Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolysed to the acid form to become biologically active. The prodrug is well absorbed through the cornea and all drug that enters the aqueous humour is hydrolysed during the passage through the cornea. Studies in humans indicate that the peak concentration in the aqueous humour is reached about 2 hours after topical administration.

Distribution
The distribution volume in humans is 0.16 ±-0.02 L/kg. The acid of latanoprost can be measured in the aqueous humour during the first 4 hours and in plasma only during the first hour after local administration.

Metabolism
Latanoprost, an isopropyl ester prodrug, is hydrolysed by esterases in the cornea to the biologically active acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to the 1, 2-dinor and 1, 2, 3, 4-tetranor metabolites via fatty acid (beta)-oxidation.

Excretion
The elimination of the acid of latanoprost from human plasma is rapid (t½ = 17 minutes) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic (beta)-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the administered dose is recovered in the urine after topical and intravenous dosing, respectively.

Indications

Latanoprost ophthalmic solution is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension.

Dosage and Administration

The recommended dosage is one drop in the affected eye(s) once daily in the evening.

The dosage of Latanoprost ophthalmic solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogues is not recommended. It has been shown that administration of these prostaglandin drug products more than once daily may decrease the intraocular pressure lowering effect or cause paradoxical elevations in IOP.

Reduction of the intraocular pressure starts approximately 3-4 hours after administration and the maximum effect is reached after 8-12 hours. Latanoprost may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.

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

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for 1 minute. This should be performed immediately following the instillation of each drop.

Contraindications

Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this product.

Warnings and Precautions

General

Latanoprost has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelids), and eyelashes, and growth of eyelashes. These changes may be permanent. Latanoprost may gradually change the eyelashes; these changes include increased length, thickness, pigmentation and number of lashes. Patients who are expected to receive treatment in only one eye should be informed about the potential for increased pigmentation of the iris, periorbital tissue and eyelashes in the treated eye and, thus, heterochromia between the eyes. The effects of increased pigmentation beyond 5 years are not known. Pigmentation is expected to increase as long as latanoprost ophthalmic solution is administered. After discontinuation of latanoprost ophthalmic solution, pigmentation of the iris is likely to be permanent while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The effects of increased pigmentation beyond 5 years are not known.

Latanoprost sterile ophthalmic solution may gradually increase the pigmentation of the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.

This change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In studies with latanoprost, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for 5 years. The effect of increased pigmentation beyond 5 years has not been evaluated. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation. The iris colour change is slight in the majority of cases and, often, not observed clinically. The incidence in patients with mixed colour irides ranged from 7% to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.

The eye colour change is due to increased melanin content in the stromal melanocytes of the iris rather than to an increase in the number of melanocytes. This change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in the affected eye but the entire iris or parts of the iris become more brownish. During clinical trials, the increase in brown iris pigment has not been shown to progress further upon discontinuation of treatment, but the resultant colour change may be permanent. It has not been associated with any symptom or pathological changes in clinical trials to date. While treatment with latanoprost ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.

Neither nevi nor freckles of the iris appear to be affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical trials. Based on 5 years clinical experience, increased iris pigmentation has not been shown to have any negative clinical sequelae and latanoprost can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, latanoprost treatment may be discontinued.

Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost.

Latanoprost may gradually change the eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment.

Latanoprost should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation.

Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or anterior chamber lenses, or in patients with known risk factors for macular oedema (such as diabetic retinopathy and retinal vein occlusion). Latanoprost should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

There is limited experience of latanoprost in chronic angle closure glaucoma, open-angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no experience of latanoprost in inflammatory and neovascular glaucoma, inflammatory ocular conditions. Latanoprost has no or little effect on the pupils, but there is no experience in acute attacks of closed angle glaucoma. Therefore, it is recommended that latanoprost should be used with caution in these conditions until more experience is obtained.

Periorbital skin discolouration has been observed, with the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and, in some cases, has reversed while continuing treatment with latanoprost sterile ophthalmic solution.

There are limited study data on the use of latanoprost during the peri-operative period of cataract surgery. Latanoprost should be used with caution in these patients.

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 the ocular epithelial surface.

Latanoprost should be used with caution in patients with a history of herpetic keratitis, and 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.

Latanoprost ophthalmic solution contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy, may cause eye irritation and is known to discolour soft contact lenses. Close monitoring is required with frequent or prolonged use of Latanoporst ophthalmic solution in patients with dry eyes, or in conditions where the cornea is compromised.

Contact lenses may absorb benzalkonium chloride; hence, the lenses should be removed before instilling latanoprost ophthalmic solution, but may be reinserted after 15 minutes.

There is limited experience from patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported in postmarketing experience. Asthmatic patients should, therefore, be treated with caution until there is sufficient experience.

In common with other eye preparations, instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

Drug Interactions

In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost. If such drugs are used they should be administered with an interval of at least 5 minutes between instillations.

There have been reports of paradoxical elevations in intraocular pressure following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

Pregnancy

Teratogenic Effects
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. The safety of this medicinal product for use in human pregnancy has not been established. It has potential hazardous pharmacological effects with respect to the course of pregnancy, and to the foetus or the neonate. Therefore, latanoporst ophthalmic solution should not be used during pregnancy.

Lactation

It is not known whether this drug or its metabolites are excreted in human milk. Latanoprost and its metabolite may pass into breast milk and latanoporst ophthalmic solution should, therefore, not be used in nursing mothers or breast-feeding should be stopped.

Pediatric Use

Safety and effectiveness in paediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Undesirable Effects

The majority of undesirable effects relate to the ocular system. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation. Other ocular adverse events are generally transient and occur on dose administration.

Adverse events are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,0000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Infections and Infestations

Not known
Herpetic keratitis.

Eye Disorders

Very Common
Increased iris pigmentation; mild-to-moderate conjunctival hyperaemia, eye irritation (burning grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes (increased length, thickness, pigmentation and number; vast majority of reports in the Japanese population).

Common
Transient punctate epithelial erosions, mostly without symptoms; blepharitis; eye pain.

Uncommon
Eyelid oedema: dry eye; keratitis; vision blurred; conjunctivitis, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid erythema, and photophobia.

Rare
Iritis/uveitis (the majority of reports in patients with concomitant predisposing factors); macular oedema including cystoid macular oedema; symptomatic corneal oedema and erosions; periorbital oedema; misdirected eyelashes, sometimes resulting in eye irritation; extra row of cilia at the aperture of the meibomian glands (distichiasis), photophobia.

Very rare
Periorbital and lid changes resulting in deepening of the eyelid sulcus, retinal artery embolus, retinal detachment, and vitreous haemorrhage from diabetic retinopathy.

Not known
Iris cyst.

Nervous System Disorders

Not known
Headache, dizziness.

Cardiac Disorders

Very Rare
Aggravation of angina in patients with pre-existing disease.

Not known
Palpitations.

Respiratory, Thoracic and Mediastinal Disorders

Common
Respiratory tract infection/ cold/flu

Rare
Asthma, asthma exacerbation and dyspnoea.

Skin and Subcutaneous Tissue Disorders

Uncommon
Skin rash/allergic skin reaction, toxic epidermal necrolysis

Rare
Localized skin reaction on the eyelids; darkening of the palpebral skin of the eyelids.

Musculoskeletal and Connective Tissue Disorders

Not known
Myalgia; arthralgia.

General Disorders and Administration Site Conditions 

Chest pain
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.

Overdosage

Apart from ocular irritation and conjunctival or episcleral hyperaemia, no other ocular side effects are known if latanoprost sterile ophthalmic solution is overdosed.

If latanoprost sterile ophthalmic solution is accidentally ingested, the following information may be useful. One bottle contains 125 micrograms latanoprost. More than 90% is metabolized during the first pass through the liver. Intravenous infusion of 3 micrograms/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical treatment and induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In monkeys, latanoprost has been infused intravenously in doses of up to 500 micrograms/kg without major effects on the cardiovascular system.

Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost when applied topically in the eyes at a dose of seven times the clinical dose of latanoprost.

If overdosage with latanoprost sterile ophthalmic solution occurs, treatment should be symptomatic.

Incompatibility

In vitro studies have shown that precipitation occurs when eye drops containing thiomersal are mixed with latanoprost sterile ophthalmic solution. If such drugs are used, the eye drops should be administered with an interval of at least 5 minutes between instillations.

Shelf-life

2 years.

Storage and Handling Instructions

Protect from light. Store unopened bottle(s) under refrigeration at 2-8°C (36-46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F) for 6 weeks.

Packaging Information

9 PM Eye Drops: Vial of 2.5 ml

Information for Patients

Patients should be informed about the possibility of iris colour change due to an increase of the brown pigment and the resultant, cosmetically different eye colouration that may occur when only one eye is treated. Iris pigmentation changes may be more noticeable in patients with green-brown, blue/grey-brown or yellow-brown irises. The increased pigmentation to the iris may be permanent.

Patients should also be informed of the possibility of eyelash changes and vellus hair changes in the treated eye, which may result in a disparity between eyes in lash length, thickness, pigmentation, and/or numberof eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.

Patients should also be informed about the possibility of darkening of eyelid skin, which may be reversible after discontinuation of latanoprost.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eyes or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eyes and subsequent loss of vision may result from using contaminated solutions. 

Patients also should be advised that if they develop an intercurrent ocular condition (e.g. trauma or infection) or have ocular surgery, they should immediately seek their physician’s advice concerning the continued use of the multi-dose container. 

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their physician’s advice. 

Patients should also be advised that latanoprost contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to administration of the ophthalmic solution, but may be reinserted 15 minutes after administration. 

If more than one topical ophthalmic drug is being used, the drugs should be administered at least 5 minutes apart.