Xalacom, eye drops 2.5 ml

Because of the different mechanism of lowering elevated intraocular pressure of timolol and latanoprost, Xalacom combined eye drops are more effective in reducing IOP in patients compared to the use of each active ingredient alone.

Latanoprost increases aqueous humor outflow without affecting aqueous humor production. Timolol decreases aqueous humor production in the ciliary epithelium without affecting cardiac muscle function.

Latanoprost penetrates easily through the cornea of the eye, maximum concentration in aqueous humor about 2 hours after injection (in monotherapy). It is almost not metabolized in the eye tissues. The elimination half-life of lathanoprost acid is 17 minutes. Metabolites are excreted with urine and have no marked biological activity.

In aqueous humor timololol is maximally concentrated one hour after injection (in monotherapy). Timolol is partially absorbed systemically, appearing in blood plasma at a concentration of 1 ng/ml after 10-20 minutes. The plasma elimination half-life is about 6 hours. It is excreted with urine.

The concentration of acid latanoprost in aqueous humor may increase in 1-4 hours after injection of Xalacom eye drops (compared to monotherapy).

Pharmacokinetics

No pharmacokinetic interaction between latanoprost and timolol maleate has been established, although 1-4 h after Xalacom administration, latanoprost acid concentration in aqueous humor was approximately 2 times higher than with monotherapy.

Latanoprost

Intake

Latanoprost, being a prodrug, penetrates well through the cornea and is hydrolyzed to its bioactive form (acid). C_max in aqueous humor is reached 2 h after topical application. Systemic bioavailability of latanoprost acid after topical application of eye drops is 45%.

Distribution

V_d is 0.16±0.02 L/kg. Latanoprost acid is determined in aqueous humor during the first 4 h, and in plasma only during the first hour after topical administration. Binding to plasma proteins is 87%.

Metabolism

Latanoprost undergoes hydrolysis in the cornea by esterases to form bioactive acid. Latanoprost acid entering the systemic bloodstream is metabolized primarily in the liver by beta-oxidation of fatty acids to form 1,2-dinor- and 1,2,3,4-tetranor metabolites.

Elimination

Latanoprost acid is rapidly excreted from the blood plasma. T_1/2 is 17 min. Plasma clearance is 0.4 L/h/kg. Systemic clearance is approximately 7 ml/min/kg. Metabolites are excreted mainly by the kidneys: after topical administration, about 88% of the dose is excreted with the urine.

Timolol maleate

Intake

The C_max of timololol maleate in aqueous humor is reached after 1 hour. Part of the dose undergoes systemic absorption and 10-20 minutes after topical administration of the drug 1 drop in each eye 1 time/day (300 mcg/day), a plasma C_max of 1 ng/mL is reached.

Metabolism and excretion

Timolol maleate is actively metabolized in the liver. T_1/2 timolol maleate from plasma is about 6 h. Metabolites, as well as some unchanged timolol maleate, are excreted by the kidneys.

Indications

Xalacom is used to reduce elevated intraocular pressure in open-angle glaucoma. It is also prescribed for increased ophthalmotonus.

Active ingredient

Latanoprost, Timolol

Composition

The eye drops are in the form of a clear, colorless solution.

Associates:

benzalkonium chloride (as a 50% solution) – 200 µg,

sodium hydrophosphate anhydrous – 2.89 mg,

sodium dihydrophosphate monohydrate – 6.39 mg,

sodium chloride – 4.1 mg,

d/i water – up to 1 ml.

How to take, the dosage

Adults and the elderly are recommended to inject 1 drop once daily into one or both eyes.

If one dose is missed, the next dose should be given at the usual time.

Interaction

There have been no specific studies on drug interactions with Xalacom eye drops.

If calcium channel blockers, beta-adrenoblockers, antiarrhythmic drugs (including amiodarin and quinidine), cardiac glycosides from the group of foxglove drugs, cholinomimetics, narcotic analgesics, monoamine oxidase inhibitors, drugs that reduce catecholamine activity, a pronounced slowing of heart rate and lowering of blood pressure may develop.

The local use of two beta-adrenoblockers or two prostaglandins is not recommended.

In a history of spontaneous hypoglycemia episodes, in diabetes mellitus (especially labile), with administration of insulin or blood glucose-lowering drugs, beta-adrenoblockers should be prescribed with caution. The drug may mask the manifestations of acute hypoglycemia.

Pupil dilation has been observed in some cases when timolol was used with adrenaline, although Xalacom as monotherapy has almost no effect on pupil size.

Special Instructions

The drug should not be used more than once a day, since more frequent use weakens the IOP-lowering effect.

If the patient uses other eye drops at the same time, they should be used at least 5 minutes apart.

The benzalkonium chloride in Xalacom Eye Drops as a preservative is absorbed into the lens material of the soft contact lens. Lenses should be removed before instillation of the drops. It is possible to put them on again after at least 15 minutes.

Latanoprost

Latanoprost can cause a gradual increase in brown pigment in the iris. The change in eye color is due to an increase in melanin in the stromal melanocytes of the iris, not an increase in the number of melanocytes themselves. In typical cases, brown pigmentation appears around the pupil and spreads concentrically to the periphery of the iris. In this case the entire iris or its parts take on a brown color. In most cases, the color change is subtle and may not be detected clinically. Increased iris pigmentation of one or both eyes is seen mostly in patients with mixed iris color, containing brown at the core. The drug has no effect on iris nevi and lentigos; no accumulation of pigment in the trabecular network or anterior chamber of the eye was noted.

In determining iris pigmentation over 5 years, there were no adverse effects of increased pigmentation even with continued latanoprost therapy. The degree of IOP reduction was similar in patients regardless of the degree of iris pigmentation. Therefore, treatment with latanoprost may be continued in cases of increased iris pigmentation, but patients should be monitored regularly and, depending on the clinical situation, treatment may be discontinued.

Augmentation of iris pigmentation is usually seen within the first year of treatment, rarely after the second or third year. This effect was not observed after the fourth year of treatment. The rate of progression of pigmentation decreases with time and stabilizes after 5 years. The effects of increased iris pigmentation have not been studied in the longer term. No increase in brown iris pigmentation has been observed after discontinuation of treatment, but the change in eye color may be irreversible.

Latanoprost has been associated with cases of darkening of the eyelid skin, which may be reversible.

Latanoprost can cause gradual changes to eyelashes and downy hair, such as lengthening, thickening, increasing pigmentation, increasing density, and changing the direction of lash growth. Eyelash changes are reversible and go away after treatment is discontinued.

Heterochromia is possible in patients who use drops to treat only one eye.

Timolol maleate

The same adverse reactions may be observed with topical use of beta-blockers as with systemic use.

Patients with a history of severe heart disease should be continuously monitored for the timely detection of symptoms of heart failure. Progression of Prinzmetal angina, peripheral and central circulatory disorders, arterial hypotension, bradycardia, fatal heart failure, and severe respiratory reactions (including fatal bronchospasm in patients with bronchial asthma) may occur with topical use of timolol maleate.

We should discuss the appropriateness of gradual withdrawal of beta-adrenoblockers before major surgery. Drugs in this group impair the ability of the heart to respond to reflex beta-adrenergic stimulation, which may increase the risk during anesthesia. Cases of prolonged severe arterial hypotension during anesthesia and difficulties in recovery and maintenance of cardiac activity have been described. During surgery, the effects of beta-blockers can be eliminated with sufficient doses of adrenoreceptor agonists.

Beta-adrenoblockers may increase the hypoglycemic effects of oral hypoglycemic agents and mask the symptoms of hypoglycemia. They should be used with caution in patients with spontaneous hypoglycemia or diabetes mellitus (especially of labile course) receiving insulin or oral hypoglycemic agents.

The therapy with beta-adrenoblockers may mask symptoms of hyperthyroidism; abrupt discontinuation of treatment may cause exacerbation of this disease.

When treated with beta-adrenoblockers in patients with a history of atopy or severe anaphylactic reactions to various allergens, an increased response may occur upon repeated exposure to these allergens. In this case epinephrine (adrenaline) in usual doses used for anaphylactic reactions may be ineffective.

In rare cases, timolol maleate causes increased muscle weakness in patients with myasthenia gravis or myasthenic symptoms (e.g., diplopia, ptosis, generalized weakness).

In the use of agents that reduce intraocular pressure, vascular detachment after filtration procedures has been described.

Impact on the ability to drive motor vehicles and operate machinery

The use of eye drops may cause transient blurring of vision. Until this effect disappears, patients should not drive a vehicle or operate complex machinery.

Contraindications

• Reactive respiratory disease (including bronchial asthma or a history of it).
• Severe COPD
• Sinus bradycardia
• AV-blockade of degree II and III .
• Clinically pronounced heart failure.
• Cardiogenic shock.
• High sensitivity to the components of the drug.

The drug is used with caution in:

• Inflammatory, neovascular, closed-angle or congenital glaucoma.
• Open-angle glaucoma combined with pseudophakia.
• Pigmentary glaucoma (due to insufficient experience with the drug).
• Aphakia, pseudophakia with rupture of the posterior lens capsule.
• In patients with known risk factors for macular edema (cases of macular edema, including cystoid edema, have been described with latanoprost treatment).

Side effects

Clinical studies have found no side effects specific to Xalacom eye drops. However, adverse events associated with the use of latanoprost and timolol are possible.

The incidence of adverse reactions is categorized as follows: very common ≥10%, common ≥1% and

Overlooking organ: very common – increased iris pigmentation; common – visual impairment, blepharitis, cataracts, conjunctivitis, conjunctival lesions (follicles, papillary conjunctival reactions, pinpoint hemorrhages, etc.), corneal lesions (erosions, pigmentation, keratitis, pitting keratitis, etc.), refractive disorders, conjunctival hyperemia, eye irritation (including burning sensation and itching in the eye), eye pain, photophobia, visual field loss, increased tear production.

Endocrine system disorders: often – diabetes mellitus.

Metabolism: often – hypercholesterolemia.

Psychiatric disorders: often – depression.

Nervous system disorders: often – headache.

Cardiovascular system: often – increase in blood pressure.

Skin and subcutaneous tissue: often – hypertrichosis, rash, itching and skin changes (irritation, dermatochalasis, etc.).

Muscular system disorders: often – arthritis.

Infections and invasions: often – sinusitis, upper respiratory tract infections and other infections.

The following are other adverse reactions which have been observed during monotherapy with individual components of the drug Xalacom^® (in addition to those mentioned above).

Latanoprost

Eye side effects: Eye irritation (burning sensation, sensation of sand in eyes, itching, tingling and sensation of foreign body); transient pitting erosions of corneal epithelium, eyelid edema, keratitis; lengthening, thickening, increasing number and increasing pigmentation of eyelashes and down hair; Iritis/veitis; macular edema (in patients with aphakia, in patients with pseudophakia with rupture of the posterior lens capsule or in patients with risk factors for macular edema), includingincluding cystoid; changes in the direction of eyelash growth, sometimes causing eye irritation; blurred vision, photophobia, changes in the periorbital area and eyelids leading to deepening of the upper eyelid sulcus, periorbital edema, iris cysts.

Systemic diseases: exacerbation of angina in patients with CHD, palpitations.

Skin and subcutaneous tissue disorders: rash, darkening of the eyelid skin and local skin reactions on the eyelids.

Nervous system disorders: dizziness.

Respiratory system: asthma (including acute attacks or exacerbation of the disease in patients with a history of bronchial asthma), shortness of breath.

Muscular system disorders: muscle pain, joint pain.

Infections and invasions: herpetic keratitis.

Others: nonspecific chest pain.

Timolol (in the form of eye drops)

Allergic reactions: systemic allergic reactions, including anaphylaxis, angioedema, anaphylactic reactions, urticaria, skin itching, localized and generalized rash.

Metabolic disorders: latent symptoms of hypoglycemia in diabetic patients.

Mental disorders: behavioral changes and mental disorders, including confusion, hallucinations, anxiety, disorientation, nervousness, symptoms of depression, memory loss, insomnia, depression and nightmares.

Nervous system disorders: cerebral ischemia, acute cerebral circulation disorders, dizziness, increased symptoms of myasthenia gravis, paresthesia, somnolence, headache, fainting.

VIight organ side: Cystoid macular edema, decreased corneal sensitivity; eye irritation symptoms and signs (e.g., burning sensation, itching, sandy feeling in eyes, increased lacrimation, redness), blepharitis, keratitis, blurred vision, dry eye mucosa, corneal erosions, choroidal detachment after filtering surgery; ptosis, visual disturbances, incl.including changes in refraction and diplopia.

Hearing and vestibular system disorders: tinnitus.

Cardiovascular system disorders: arrhythmia, bradycardia, AV blockade, chronic heart failure, cardiac arrest, intracardiac conduction block, palpitation, angina progression, intermittent claudication, cold hands and feet, BP decrease, Raynaud’s syndrome.

Respiratory system: bronchospasm (mainly in patients with previous bronchospastic disorders), cough, dyspnea, nasal congestion, pulmonary edema and respiratory failure.

Digestive system disorders: diarrhea, dry mouth, impaired sense of taste, dyspepsia, nausea, vomiting, abdominal pain, retroperitoneal fibrosis.

Skin and subcutaneous tissue disorders: alopecia, pseudopemphigoid, skin rash, psoriasis-like rash or exacerbation of psoriasis.

Muscular system disorders: SLE, myalgia.

Social system disorders: decreased libido, impotence, sexual dysfunction and Peyronie’s disease.

Others: anorexia, asthenia/fatigue, chest pain, edema.

In some patients with significant corneal damage, very rare cases of corneal calcification have been reported due to the use of phosphate-containing eye drops.

Overdose

Latanoprost

Symptoms: Apart from eye irritation and conjunctival hyperemia, there are no known adverse visual changes in latanoprost overdose.

In case of accidental ingestion of latanoprost, it should be noted that 1 vial of 2.5 ml of solution contains 125 mcg of latanoprost. More than 90% of the drug is metabolized during “first passage” through the liver. IV infusion at a dose of 3 µg/kg in healthy volunteers caused no symptoms, but nausea, abdominal pain, dizziness, fatigue, hot flashes, and sweating were observed when administered at doses of 5.5-10 µg/kg. These symptoms resolved 4 h after stopping the infusion. In patients with moderate bronchial asthma, administration of latanoprost at 7 times therapeutic dose did not cause bronchospasm.

Timolol maleate

Symptoms: There have been cases of unintentional overdose of timololol maleate eye drops resulting in effects similar to those seen with systemic use of beta-adrenoblockers: dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest.

In an in vitro study, timolol maleate has been shown to be easily eliminated from plasma or whole blood during dialysis. In patients with renal insufficiency, timolol maleate was dialyzed worse.

Treatment: in case of Xalacom overdose symptomatic therapy is administered.

Pregnancy use

Controlled adequate studies of the use of the drug in pregnant women have not been conducted. Use is possible only when the estimated benefit to the mother exceeds the potential risk to the fetus.

Latanoprost and its metabolites may be excreted with breast milk; timolol maleate was also detected in breast milk when used in the form of eye drops. If it is necessary to use the drug during lactation, discontinuation of breastfeeding should be considered, considering the risk of serious adverse reactions in breastfed infants and the importance of the drug for the mother.

Pediatric use

The safety and effectiveness of Xalacom in children has not been established.

Similarities

Duoprost