Xalacom - instructions for use, dose, side effects, contraindications

Active substanceLatanoprost + TimololLatanoprost + Timolol

Similar drugsTo uncover

Duoprost

drops d / eye

K.O. Ромфарм Компани С.Р.Л. Romania

Xalacom®

drops d / eye

Pfizer IFG Belgium N.V. Belgium

Dosage form: & nbspeye drops

Composition:

1 ml of the solution contains:

active substances: latanoprost - 50 mcg, timolol maleate - 6.83 mg (equivalent to 5 mg timolol);

Excipients: benzalkonium chloride (as a 50% solution) 200 μg, sodium hydrogen phosphate anhydrate 2.89 mg, sodium dihydrogen phosphate monohydrate 6.39 mg, sodium chloride 4.10 mg, water for injection up to 1 ml.

Description:

A clear, colorless solution.

Pharmacotherapeutic group:Anti-glaucoma combined (prostaglandin F2-alpha analogue synthetic + beta adrenoblocker)

ATX: & nbsp

S.01.E.D. Beta-blockers

S.01.E.D.51 Timolol in combination with other drugs

Pharmacodynamics:

The composition of the drug Xalacom® includes two active components - latanoprost and timolol. The mechanism of reducing the increased intraocular pressure (IOP) in these components is different, which provides an additional reduction in IOP in comparison with the effect achieved with the use of each of these components in the form of monotherapy. Latanoprost - analog prostaglandin F2_α is a selective prostanoid receptor agonist FP and reduces IOP by increasing the outflow of watery moisture, mainly by the uveoscleral route, and also through the trabecular network. Determined that latanoprost does not have a significant effect on the production of aqueous humor and the permeability of the hemato-ophthalmic barrier. During short-term treatment latanoprost does not cause leakage of fluorescein into the posterior segment of the eye under pseudophakia. When used in therapeutic doses latanoprost has no significant pharmacological effect on the cardiovascular and respiratory systems.

Timolol - non-selective β1- and β2-adrenoblocker, which does not have significant internal sympathomimetic activity, does not exert a direct inhibitory effect on the myocardium or local anesthetic (membrane-stabilizing) effect.

Blockade of β-adrenergic receptors causes a decrease in cardiac output in healthy people and patients with heart disease. In patients with severe myocardial dysfunction, β-adrenoblockers can inhibit the stimulating effect of the sympathetic nervous system necessary for adequate cardiac function.

Blockade of β-adrenergic receptors in the bronchi and bronchioles leads to an increase in the resistance of the respiratory tract under the influence of the parasympathetic nervous system. Such an effect can be dangerous for patients with bronchial asthma and other bronchospastic diseases (see section "Contraindications" and "Special instructions").

The use of timolol in the form of eye drops causes a decrease in elevated and normal IOP regardless of the presence or absence of glaucoma. Increased IOP is the main risk factor for glaucomatous prolapse of visual fields. The higher the IOP, the higher the probability of glaucomatous prolapse of visual fields and damage to the optic nerve.

The exact mechanism for reducing IOP due to timolol is not established. The results of tonography and fluorophotometry indicate that the main mechanism of action can be associated with a decrease in the formation of watery moisture. However, some studies have also noted a slight increase in outflow. In addition, the mechanism of inhibition of increased synthesis of cyclic AMP caused by endogenous β-adrenergic stimulation is also possible.There was no evidence of any influence of timolol on the permeability of the hemato-ophthalmic barrier.

The combination of latanoprost and timolol starts within an hour, and the maximum effect is observed within 6-8 hours.

With repeated use, an adequate decrease in IOP persists for 24 hours after administration.

Pharmacokinetics:

Pharmacokinetic interactions between latanoprost and timolol have not been established, although 1-4 hours after the combined preparation, the concentration of latanoprost acid in aqueous humor was approximately twice that of monotherapy.

Latanoprost:

Suction

Latanoprost, being a prodrug form, is absorbed through the cornea, where its hydrolysis occurs to a biologically active acid. It was found that the concentration in watery moisture reaches a maximum about two hours after topical application.

Distribution

The volume of distribution is 0.16 ± 0.02 l / kg. Latanoprost acid is determined in aqueous humor during the first 4 hours, and in plasma only within the first hour after topical application.

Metabolism

Latanoprost undergoes hydrolysis in the cornea under the action of esterases to form a biologically active acid. Latanoprost acid, entering the systemic bloodstream, is metabolized mainly in the liver by β-oxidation of fatty acids to form 1,2-dinor and 1,2,3,4-tetranor metabolites.

Excretion

Latanoprost acid is rapidly excreted from the plasma - half-life (t1/ 2) = 17 min. Plasma clearance is 0.40 l / h / kg. Systemic clearance is approximately 7 ml / min / kg. After topical application of eye drops, the systemic bioavailability of latanoprost acid is 45%. The connection with plasma proteins is 87%. Metabolites are excreted mainly by the kidneys: after topical application with urine, approximately 88% of the administered dose is excreted.

Timolol:

The concentration of timolol in aqueous humor reaches a maximum about 1 hour after the application of eye drops. Part of the dose is systemically absorbed, and the maximum plasma concentration of 1 ng / ml is reached 10-20 minutes after the drug is administered one drop in each eye once a day (300 μg / day). The half-life of timolol from the plasma is about 6 hours. Timolol is actively metabolized in the liver.Metabolites, as well as a certain amount of unchanged timolol, are excreted in the urine.

Indications:

Decreased elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension with insufficient effectiveness of monotherapy with individual components of the drug.

Contraindications:

Respiratory diseases of the respiratory tract, incl. bronchial asthma (or indication of its presence in an anamnesis), COPD severe course; sinus bradycardia, sinus node weakness syndrome, sinoatrial block, atrioventricular blockade of II-III degree without control of the artificial pacemaker, clinically expressed heart failure, cardiogenic shock; hypersensitivity to latanoprost, timolol or other components of the drug, children under 18 years of age (safety and efficacy not established).

Carefully:

Inflammatory, neovascular, angle-closure glaucoma, open-angle glaucoma in combination with pseudophakia, pigmentary glaucoma (due to lack of sufficient experience of the drug); aphakia, pseudophakia with a ruptured posterior capsule of the lens,patients with known risk factors for macular edema (in the treatment with latanoprost, cases of development of macular edema, including cystoid edema); herpetic keratitis in the anamnesis; atrioventricular blockade of the 1st degree (β-adrenoblockers negatively affect the time of impulse in the heart muscle); peripheral circulatory disorders (for example, severe forms of Raynaud's syndrome or Raynaud's disease).

Xalacom® should be avoided in patients with active form of herpetic keratitis and recurrent herpetic keratitis, especially associated with the use of prostaglandin analogues F2_α.

Timolol should be used with caution in patients with chronic obstructive pulmonary disease and only in cases where the potential benefit of using the drug for the patient exceeds the risk.

Caution should be applied to Xalac® in patients with corneal disease, since the drug may cause dryness of the eye mucosa.

Pregnancy and lactation:

Adequate controlled studies in pregnant women have not been conducted.

When carrying out epidemiological studies using β-blockersthere were no cases of malformations of the fetus, but the risk of intrauterine growth retardation was increased. In addition, the symptoms of β-adrenergic blocking action (such as bradycardia, lowering of blood pressure, respiratory function disorder and hypoglycemia) were detected in newborns whose mothers received β-adrenoblockers during pregnancy. In the case of a pregnant woman receiving therapy with β-blockers, careful monitoring of the condition of the newborn should be carried out in the first days after birth. In this regard, the use of Xalac® during pregnancy is possible only in cases where the expected benefit for the mother exceeds the potential risk to the fetus or child.

Latanoprost and its metabolites can be excreted into breast milk. Timolol, when applied in the form of eye drops, were also found in breast milk. Given the risk of developing serious adverse reactions in newborns who are breastfeeding, and the importance of using the drug for the mother, either stop breastfeeding or stop the drug.

Dosing and Administration:

Adult (including the elderly) - one drop in the affected eye (a) once a day. As with any eye drops, in order to reduce the possible systemic effect of the drug, immediately after instillation of each drop, it is recommended to apply pressure to the lower lacrimal point located at the inner corner of the eye in the lower eyelid. This must be done within 2 minutes.

Side effects:

The frequency of unwanted reactions is represented by the following classification:

Very frequent ≥10%

Frequent ≥1% and <10%

Infrequent ≥0.1% and <1%

Rare ≥0.01% and <0.1%

Very rare <0.01%

From the side of the organ of vision: very frequent - increased pigmentation of the iris; frequent - blurred vision, blepharitis, cataracts, conjunctivitis, conjunctival lesions (follicles, conjunctival papillary reactions, pinpoint hemorrhages, etc.), cornea lesions (erosion, pigmentation, keratitis, spot keratitis, etc.), refractive disorders, conjunctival hyperemia, irritation eyes (including a burning sensation and itching in the eyes), pain in the eyes, photophobia, loss of visual fields, increased tearing.

Infections: frequent - sinusitis, infections of the upper respiratory tract and other infections.

Metabolic and nutritional disorders: frequent - diabetes, hypercholesterolemia.

Mental disorders: frequent depression.

From the nervous system: frequent - headache.

Vascular disorders: frequent increases in blood pressure.

From the skin and subcutaneous tissues: frequent - hypertrichosis, rash, skin itching and skin changes (irritation, dermatochalazion, etc.).

From the side of the musculoskeletal system and connective tissue: frequent - arthritis.

The following are other adverse events that have been observed with monotherapy with individual components of Xalac® (other than those mentioned above).

Latanoprost:

From the side of the organ of vision: irritation of the eyes (burning sensation, sensation of sand in the eyes, itching, tingling and sensation of foreign body); transient point erosions of the epithelium of the cornea, edema of the eyelids, keratitis; lengthening, thickening, increasing the number and increasing pigmentation of eyelashes and gun hair; iritis / uveitis; macular edema (in patients with aphakia, in patients with pseudophakia with rupture of the posterior capsular lens or in patients with risk factors for development of macular edema), incl. cystoid; changing the direction of growth of eyelashes, sometimes causing eye irritation; blurred vision, photophobia, changes in the periorbital area and eyelids, leading to deepening of the furrow of the upper eyelid, periorbital edema, iris cysts.

From the cardiovascular system: exacerbation of angina pectoris patients with ischemic heart disease, palpitations.

From the skin and subcutaneous tissues: skin rash, darkening of the skin of the eyelids and local skin reactions on the eyelids.

From the nervous system: dizziness.

On the part of the respiratory system: asthma (including acute attacks or exacerbation of the disease in patients with bronchial asthma in the anamnesis), dyspnea.

From the side of the musculoskeletal system and connective tissue: pain in the muscles / joints.

General and local reactions: nonspecific pain in the chest.

Infections: herpetic keratitis.

Timolol (in the form of eye drops):

From the immune system: systemic allergic reactions, including anaphylaxis, angioedema, anaphylactic reactions, urticaria, skin itching, localized and generalized rash.

Metabolic and nutritional disorders: anorexia, hidden symptoms hypoglycemia in patients with sugar diabetes.

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

From the nervous system: cerebral ischemia, acute disorders of cerebral circulation, dizziness, increased myasthenia gravis symptoms gravis, paresthesia, drowsiness, headache, fainting.

From the side of the organ of vision: cystoid macular edema, decrease sensitivity of the cornea; symptoms and signs of eye irritation (eg, burning sensation, itching, sensation of sand in the eyes, increased lacrimation, redness), blepharitis, keratitis, blurred vision, dry eye mucosa, corneal erosion, vascular closure after filtration surgical interventions; ptosis, visual impairment, including changes in refraction and diplopia.

From the organ of hearing and the vestibular apparatus: noise in ears.

From the heart: arrhythmia, bradycardia, atrioventricular blockade, chronic heart failure, cardiac arrest, blockade of intracardiac conduction, palpitations, progression of angina pectoris.

Vascular disorders: intermittent claudication, coldness of hands and feet, lowering blood pressure, Raynaud's syndrome.

On the part of the respiratory system: bronchospasm (mainly in patients with previous bronchospastic diseases), cough, shortness of breath, nasal congestion, pulmonary edema and respiratory failure.

From the gastrointestinal tract: diarrhea, dry mucosa oral cavity, taste disorders, dyspepsia, nausea, vomiting, abdominal pain, retroperitoneal fibrosis.

From the skin and subcutaneous tissues: alopecia, pseudopemphigoid, skin rash, psoriasis-like rash or exacerbation of psoriasis.

From the side of the musculoskeletal system and connective tissue: systemic lupus erythematosus and myalgia.

On the part of the reproductive system and mammary glands: decreased libido, impotence, violation of sexual function and Peyronie's disease.

General and local: asthenia / fatigue, chest pain, swelling.

In some patients with significant damage to the cornea, very rare cases of calcification of the cornea due to the use of phosphate-containing eye drops were recorded.

Overdose:

Below is information on an overdose of two components of the drug:

Latanoprost

In addition to eye irritation and conjunctival hyperemia, other unwanted changes on the part of the eye in case of an overdose of latanoprost are not known.

If you randomly take Latanoprost inwards, you should consider the following information: one bottle with 2.5 ml of solution contains 125 μg of latanoprost. More than 90 % Latanoprost is metabolized on first passage through the liver. Intravenous infusion at a dose of 3 μg / kg in healthy volunteers did not cause any symptoms, however, upon administration doses of 5.5-10 mcg / kg, nausea, abdominal pain, dizziness, fatigue, "hot flashes" and sweating were observed. These symptoms are resolved 4 hours after the infusion has stopped. In patients with bronchial asthma of moderate severity, the administration of latanoprost in the eye at a dose 7 times higher than the therapeutic dose did not cause bronchospasm.

Timolol

The cases of unintentional overdose of eye drops of timolol are described, as a result of which systemic effects similar to those in systemic application were observed β- adrenoblockers: dizziness, headache, dyspnea, bradycardia, bronchospasm and cardiac arrest (see section "Side effect").

In the study in vitro it was shown that in dialysis timolol easily removed from the plasma or whole blood.

In patients with renal insufficiency timolol dialysis was worse.

In case of an overdose, symptomatic treatment is performed.

Interaction:

The interaction of Xalacom® with other drugs has not been specifically studied. With the use of Xalacom ® in patients receiving β-adrenoblocker inside, a more pronounced decrease in IOP or an increase in systemic manifestations of β-adrenoblockers is possible, therefore simultaneous topical application of two or more β-blockers is not recommended.

With the simultaneous instillation of two analogues of prostaglandins in the eyes, a paradoxical increase in IOP is described, therefore, simultaneous use of two or more prostaglandins, their analogs or derivatives is not recommended.

With the simultaneous use of timolol with epinephrine, mydriasis sometimes developed.

When tymolol is combined with the drugs listed below, an additive effect is possible with a decrease in blood pressure and / or severe bradycardia:

- blockers of "slow" calcium channels;

- drugs that cause a decrease in the content of catecholamines, or β-adrenoblockers:

- antiarrhythmic drugs (including amiodarone);

- cardiac glycosides;

- guanethidine.

A reported increase in the effect of systemic β-blockers (eg, reduction in heart rate, depression) with simultaneous application of isoenzyme inhibitors CYP2D6 (eg, quinidine, fluoxetine, paroxetine) and timolol.

β-adrenoblockers can enhance the hypoglycemic effect of hypoglycemic drugs.

With a sudden withdrawal of clonidine, there is an increase in blood pressure. This reaction can be enhanced by simultaneous use with β-blockers.

Special instructions:

The drug Xalacom® should not be used more than once a day, as more frequent administration of latanoprost leads to a weakening of the IOP-lowering effect.

If you miss one dose, the next dose should be administered at the usual time.

If the patient simultaneously uses other eye drops, they should be applied at intervals of at least 5 minutes.

The composition of the drug Xalacom® is benzalkonium chloride, which can be absorbed by contact lenses.There are reports of the development of point keratopathy and / or toxic ulcer keratopathy, and also with the use of benzalkonium chloride, eye irritation and discoloration of soft contact lenses may occur. It is recommended to carefully monitor the condition of patients who use Xalac® frequently or for a long time, which have dry eye mucosa or corneal damage. Before dropping drops, contact lenses must be removed and reinstalled after 15 minutes.

Latanoprost

Latanoprost can cause a gradual increase in the content of brown pigment in the iris. As with the application of latanoprost in the form of eye drops, with the use of Xalac®, the increase in iris pigmentation was noted in 16-20% of cases among all patients who received Xalac® within a year (photo-based assessment). The change in eye color is due to an increase in melanin content in the stromal melanocytes of the iris, rather than an increase in the number of melanocytes themselves. In typical cases, brown pigmentation appears around the pupil and concentrates on the periphery of the iris.In this case, the entire iris or parts of it become brown. In most cases, discoloration is negligible and may not be clinically established. The enhancement of the iris pigmentation of one or both eyes is observed, mainly, in patients with a mixed color of the iris, which is based on a brown color. The drug has no effect on the nevi and lentigo iris: no accumulation of pigment in the trabecular network or in the anterior chamber of the eye.

In determining the degree of pigmentation of the iris for more than 5 years, no undesirable effects of pigmentation enhancement have been detected even with the continuation of latanoprost therapy. In patients, the degree of IOP decrease was the same regardless of the presence or absence of enhancement of the pigmentation of the iris. Therefore, treatment with latanoprost can continue in cases of increased pigmentation of the iris. Such patients should be under regular supervision and, depending on the clinical situation, treatment can be discontinued.

Strengthening of the pigmentation of the iris is usually observed during the first year after the initiation of treatment, rarely - during the second or third year.After the fourth year of treatment this effect was not observed. The rate of progression of pigmentation decreases with time and stabilizes after 5 years. In more distant terms, the effects of increased iris pigmentation were not studied. After the cessation of treatment of the enhancement of brown pigmentation, the iris was not noted, however, the discoloration of the eyes may be irreversible. In connection with the use of latanoprost, cases of darkening of the eyelid skin, which can be reversible, are described.

Latanoprost can cause gradual changes in eyelashes and fleece hair, such as lengthening, thickening, increasing pigmentation, increasing the density and changing the direction of growth of the eyelashes. The eyelash changes are reversible and pass after the cessation of treatment.

Patients who apply drops to only one eye may develop heterochromia, which may also be irreversible.

Timolol

With topical application of β-blockers, the same undesirable reactions can be observed, as in their systemic application. Patients with severe heart disease should be monitored continuously in order to detect symptoms of heart failure in a timely manner.With topical application of timolol, the following reactions from the heart and respiratory system may occur: progression of Prinzmetal angina, as well as peripheral and central circulatory disorders, hypotension, heart failure with fatal outcome, severe reactions from the respiratory system, incl. bronchospasm with fatal outcome in patients with bronchial asthma, bradycardia.

Before carrying out extensive surgical intervention, the expediency of gradual abolition of β-adrenoblockers should be discussed. Preparations of this group disrupt the ability of the heart to respond to the reflex β-adrenergic stimulation, which can increase the risk with general anesthesia. There are cases of prolonged heavy drop in blood pressure during anesthesia and difficulties in restoring and maintaining heartbeats. During the operation, the effects of β-blockers can be eliminated with sufficient doses of adrenoreceptor agonists.

Drugs with β-adrenergic blocking effect can block the systemic agonistic effect, for example epinephrine. An anesthesiologist must be warned that the patient is receiving timolol.

β-blockers can increase the hypoglycemic effect of antidiabetics and mask the symptoms and manifestations of hypoglycemia. They should be used with caution in patients with spontaneous hypoglycemia or diabetes mellitus (especially the labile course) receiving insulin or hypoglycemic agents for ingestion.

Therapy with β-blockers can mask some of the main symptoms and manifestations of hyperthyroidism. A sharp cessation of treatment can cause an exacerbation of this disease.

In the treatment of β-adrenergic blockers in patients with atopy or severe anaphylactic reactions to various allergens in an anamnesis, an increase in the response is possible upon repeated contact with these allergens. Wherein epinephrine in usual doses, used for arresting anaphylactic reactions, may prove ineffective.

In rare cases timolol caused increased muscle weakness in patients with myasthenia gravis gravis or myasthenic symptoms (eg, diplopia, ptosis, generalized weakness).

With the use of agents that reduce IOP, cases of detachment of the choroid after filtration procedures are described - fistulization operations (trabeculectomy and itsmodifications, sinusotomy with diathermotrabekulospazis, non-penetrating deep sclerectomy and other fistulizing operations that create new or stimulate existing ways of outflow of intraocular fluid).

Effect on the ability to drive transp. cf. and fur:

The use of eye drops can cause a transient blurred vision. While this effect does not disappear, patients should not drive a car or use sophisticated technology.

Form release / dosage:Eye drops.

Packaging:

For 2.5 ml of the solution (drops of the eye) in the dropper bottle (low density polyethylene) with a screw cap and a safety cap without a thread with the control of the first opening; for 1 vial of a dropper with instructions for use in a cardboard pack. On the front side of the cardboard bundle, for the purpose of controlling the first opening, a perforated line is placed, resembling the outline of semirings; the side surfaces of the pack tightly adhere to the packaging of the preparation.

Storage conditions:

Store at + 2 - + 8 ° C in a dark place.

The opened vial should be stored at a temperature not exceeding + 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years

Opened vial should be used within 4 weeks.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013924 / 01

Date of registration:04.04.2008

The owner of the registration certificate:Pfizer IFG Belgium N.V.Pfizer IFG Belgium N.V. Belgium

Manufacturer: & nbsp

PFIZER MFG. BELGIUM, N.V. Belgium

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp17.11.2015

Illustrated instructions

Instructions

Xalacom® (Xalacom®)