Composition, form of production and packaging
Eye drops in the form of a clear, colorless solution.
latanoprost 50 Ојg
timolol maleate 6.83 mg,
which corresponds to the content of timolol 5 mg
Excipients: benzalkonium chloride (as a 50% solution) - 200 Ојg, sodium hydrogen phosphate anhydrous - 2.89 mg, sodium dihydrogen phosphate monohydrate - 6.39 mg, sodium chloride - 4.1 mg, water d / and - up to 1 ml.
2.5 ml - a bottle-dropper polyethylene (1) - packs cardboard with the control of the first opening.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
Antiglaucoma combined preparation, which includes two active components - latanoprost and timolol. The mechanism of reducing elevated IOP in latanoprost and timolol is different, which provides an additional decrease in IOP in comparison with the effect of using each of these components as monotherapy.
Latanoprost - an analogue of prostaglandin F 2? - is a selective agonist of the prostanoid FP receptors and reduces IOP by increasing the outflow of aqueous humor, mainly by the uveoscleral route, and also through the trabecular network. Latanoprost has no significant effect on the production of aqueous humor and the permeability of the hemato-ophthalmic barrier.
During a short-term treatment, latanoprost does not cause fluorescein to leak into the posterior segment of the eye under pseudophakia. When used in therapeutic doses, it has no significant pharmacological effect on the cardiovascular and respiratory systems.
Timolol is a non-selective beta- 1 and beta- 2- adrenergic blocker. Does not have significant internal sympathomimetic activity, does not have a direct depressive effect on the myocardium, does not have membrane stabilizing and local anesthetic activity.
Blockade of? -adrenoceptors causes a decrease in cardiac output in healthy people and patients with heart disease. In patients with severe myocardial dysfunction, beta-adrenoblockers can inhibit the stimulating effect of the sympathetic nervous system necessary for adequate cardiac function.
Blockade of? -adrenoceptors in the bronchi and bronchioles leads to an increase in the resistance of the respiratory tract under the influence of the parasympathetic nervous system. This effect may be dangerous for patients with bronchial asthma and other bronchospastic diseases.
The use of timolol maleate 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 of IOP decrease under the action of timolol maleate is not established. The results of tonography and fluorometry indicate that the main mechanism of action can be associated with a decrease in the formation of watery moisture. However, in some studies, a small increase in the outflow of aqueous humor has also been noted. In addition, the inhibition of increased synthesis of cyclic AMP caused by endogenous ОІ-adrenergic stimulation is possible. There was no evidence of any influence of timolol on the permeability of the hemato-ophthalmic barrier.
The effect of the drug XalacВ® begins within the first hour after application, the maximum effect is observed within 6-8 hours. With repeated use, an adequate decrease in IOP persists for 24 hours after administration.
The pharmacokinetic interaction between latanoprost and timolol maleate has not been established, although 1-4 hours after the application of Xalacom, the concentration of latanoprost acid in aqueous humor was approximately 2 times higher than in monotherapy.
Latanoprost, being a prodrug, penetrates well through the cornea, while hydrolyzing to a biologically active form (acid). C max in aqueous humor is achieved 2 hours after topical application. Systemic bioavailability of latanoprost acid after topical application of eye drops is 45%.
V d is 0.16 В± 0.02 l / kg. Latanoprost acid is determined in aqueous humor during the first 4 hours, and in blood plasma - only within the first hour after topical application. Binding to plasma proteins is 87%.
Latanoprost is hydrolyzed in the cornea of вЂ‹вЂ‹the eye under the influence of esterases to form a biologically active acid. Latanoprost acid, entering the systemic bloodstream, is metabolized mainly in the liver by beta-oxidation of fatty acids to form 1,2-dinor- and 1,2,3,4-tetranor metabolites.
The acid of latanoprost is rapidly excreted from the blood plasma. T 1/2 is 17 minutes. Plasma clearance is 0.4 l / h / kg. Systemic clearance is approximately 7 ml / min / kg. Metabolites are excreted mainly by the kidneys: after local application with urine, about 88% of the dose is excreted.
C max timolol maleate in watery moisture is achieved after 1 hour. Part of the dose is systemically absorbed and after 10-20 minutes after topical application of the drug 1 drop in each eye 1 time / day (300 Ојg / day) in plasma is achieved C max , which is 1 ng / ml.
Metabolism and excretion
Timolol maleate is actively metabolized in the liver. T 1/2 of thymolol maleate from the plasma is about 6 hours. Metabolites, as well as some unchanged timolol maleate, are excreted by the kidneys.
- to reduce the increased intraocular pressure in patients with open-angle glaucoma or increased ophthalmotonus with insufficient efficacy of monotherapy with latanoprost or timolol.
Adults (including elderly patients) - 1 drop to the affected eye (a) 1 time / day.
As with any eye drops, in order to reduce the possible systemic effect of the drug, immediately after instillation each drop is recommended to press on the lower lacrimal point, located at the inner corner of the eye in the lower eyelid, for 2 minutes.
The incidence of adverse reactions is represented by the following classification: very often? 10%, often? 1% and <10%, infrequently? 0.1% and <1%, rarely? 0.01% and <0.1%, very rarely <0.01%.
From the side of the organ of vision: very often - increased pigmentation of the iris; often - 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 burning sensation and itching in the eyes), pain in the eyes, photophobia, loss of visual fields, increased tearing.
On the part of the endocrine system: often - diabetes.
From the side of metabolism: often - hypercholesterolemia.
Mental disorders: often - depression.
From the nervous system: often - a headache.
From the cardiovascular system: often - increased blood pressure.
From the skin and subcutaneous tissues: often - hypertrichosis, rash, skin itch and skin changes (irritation, dermatochalasis, etc.).
From the musculoskeletal system: often - arthritis.
Infections and invasions: often - sinusitis, upper respiratory infections and other infections.
Other undesirable reactions that were observed with monotherapy with the individual components of the XalacВ® preparation (other than those mentioned above) are listed below.
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 in patients with IHD, palpitation.
From the skin and subcutaneous tissues: a 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 musculoskeletal system: pain in the muscles, pain in the joints.
Infections and invasions: herpetic keratitis.
Other: nonspecific chest pain.
Timolol (in the form of eye drops)
Allergic reactions: systemic allergic reactions, incl. anaphylaxis, angioedema, anaphylactic reactions, urticaria, itching, localized and generalized rash.
From the side of metabolism: the hidden symptoms of hypoglycemia in patients with diabetes mellitus.
Mental disorders: behavioral changes and mental disorders, incl. 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 symptoms of myasthenia gravis, paresthesia, drowsiness, headache, fainting.
From the side of the organ of vision: cystoid macular edema, a decrease in the sensitivity of the cornea; Symptoms and signs of eye irritation (for example, burning sensation, itching, sensation of sand in the eyes, increased lachrymation, redness), blepharitis, keratitis, blurred vision, dry eyes, corneal erosion, vascular closure after filtration surgical interventions; ptosis, visual impairment, incl. change refraction and diplopia.
From the side of the organ of hearing and the vestibular apparatus: noise in the ears.
From the cardiovascular system: arrhythmia, bradycardia, AV blockade, chronic heart failure, cardiac arrest, blockade of intracardiac conduction, palpitations, progression of angina pectoris, intermittent claudication, coldness of hands and feet, lowering of 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.
On the part of the digestive system: diarrhea, dry mouth, dyspnoea, dyspepsia, nausea, vomiting, abdominal pain, retroperitoneal fibrosis.
From the skin and subcutaneous tissues: alopecia, pseudo-pemphigoid, skin rash, psoriasis-like rash or exacerbation of psoriasis.
From the musculoskeletal system: SLE, myalgia.
On the part of the reproductive system: decreased libido, impotence, sexual dysfunction and Peyronie's disease.
Other: anorexia, 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.
- Respiratory diseases of the respiratory tract (including bronchial asthma or indication of its presence in the anamnesis);
- COPD severe course;
- sinus bradycardia;
- Sinoatrial blockade;
- AV blockade II and III degree without the control of an artificial pacemaker;
- clinically expressed heart failure;
- cardiogenic shock;
- children and adolescents under 18 years of age (safety and efficacy not established);
- hypersensitivity to latanoprost, timolol or auxiliary components of the drug.
With caution apply the drug with inflammatory, neovascular, zakratougolnoy glaucoma, open-angle glaucoma in combination with pseudophakia, pigmentary glaucoma (due to lack of experience in using the drug); aphakia, pseudophakia with a rupture of the posterior capsule of the lens; in 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; AV-blockade I degree (beta-adrenoblockers adversely affect the timing of the pulse in the heart muscle); peripheral circulatory disorders (for example, severe forms of Raynaud's syndrome or Raynaud's disease); In patients with corneal diseases, the drug may cause dryness of the eye mucosa.
Should you avoid using XalacВ® in patients with active form of herpetic keratitis and recurrent herpetic keratitis, especially associated with the use of prostaglandin F2 analogues ? .
Timolol should be used with caution in patients with COPD and only in cases where the potential benefit of using the drug for the patient exceeds the risk.
PREGNANCY AND LACTATION
Adequate controlled trials of drug use in pregnant women have not been conducted.
When conducting epidemiological studies with the use of beta-adrenoblockers, there were no cases of fetal malformations, but the risk of intrauterine development delay was increased. In addition, the symptoms of beta-adrenergic blocking action (such as bradycardia, decreased blood pressure, impaired respiratory function and hypoglycemia) were detected in newborns whose mothers received beta-blockers during pregnancy. If a pregnant woman received beta-blocker therapy, careful monitoring of the condition of the newborn should be carried out in the first days after birth. In this regard, the use of the drug XalacВ® in pregnancy is possible only in those cases where the intended use for the mother exceeds the potential risk to the fetus.
Latanoprost and its metabolites can be excreted in breast milk; Timolol maleate, when applied in the form of eye drops, was 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, if you need to use the drug during lactation, you should decide whether to stop breastfeeding or stop the drug.
APPLICATION FOR CHILDREN
Contraindicated use of the drug in children and adolescents under 18 years (safety and efficacy of the application are not established).
XalacВ® should not be used more than 1 time / day, as more frequent use leads to a weakening of the effect of reducing IOP.
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 with an interval of at least 5 minutes.
XalacВ® contains benzalkonium chloride, which can be adsorbed on contact lenses. There are reports of the development of point keratopathy and / or toxic ulcer keratopathy; Also, when using benzalkonium chloride, eye irritation and discoloration of soft contact lenses may occur. It is recommended to carefully monitor the condition of patients who use XalacВ® frequently or for a long time, which have a dry eye mucosa or conditions that damage the cornea. Before dropping drops, contact lenses should be removed and then installed after 15 minutes.
Latanoprost can cause a gradual increase in the content of brown pigment in the iris. As with the use of latanoprost in the form of eye drops, with the use of XalacВ®, the increase in iris pigmentation was noted in 16-20% of cases among all patients who received the drug during the year (evaluation based on photographs). The change in eye color is due to the increase in the number of melanin in the stromal melanocytes of the iris, rather than the 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 pigmentation of the iris 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 does not affect the nevi and lentigo iris; The accumulation of pigment in the trabecular network or the anterior chamber of the eye is not noted.
In determining the 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 decrease in IOP was the same regardless of the degree of pigmentation of the iris. Therefore, treatment with latanoprost can be continued in cases of increased pigmentation of the iris, but patients should be under regular supervision and, depending on the clinical situation, treatment can be discontinued.
The increase in pigmentation of the iris is usually observed during the first year after the initiation of treatment, rarely after 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 cessation of treatment gain brown pigmentation of the iris is not mentioned, but the change in eye color may be irreversible.
In connection with the application of latanoprost described cases of skin darkening age, which may be reversible.
Latanoprost may cause a gradual change eyelashes and vellus hair, such as lengthening, thickening, increased pigmentation, increased density and change in the direction of growth of eyelashes. Eyelash changes are reversible and disappear after cessation of treatment.
Patients who use the drops for the treatment of only one eye, may develop heterochromia.
When applied topically, beta-blockers may occur such as undesirable reactions as in systemic administration.
Patients with severe heart disease history should be constantly watching for timely detection of the symptoms of heart failure. The local application of timolol maleate can occur progression Prinzmetal angina, peripheral and central circulatory disorders, hypotension, bradycardia, cardiac failure fatal, severe reaction from the respiratory system (including fatal bronchospasm in patients with bronchial asthma patients) .
Before performing extensive surgery should discuss the desirability of gradual withdrawal of beta-blockers. Drugs in this group violate the ability of the heart to the reflex response to beta-adrenergic stimulation, which can increase the risk of anesthesia. There are cases of protracted severe hypotension during anesthesia, and difficulties in the restoration and maintenance of heart activity. During surgery, the effects of beta-blockers may be eliminated using adequate doses adrenoceptor agonists.
Drugs with beta-adrenoceptor blocking effect can block the agonist effect of systemic drugs such as epinephrine. Therefore it is necessary to warn the anesthetist that the patient is receiving timolol.
Beta-blockers may enhance the hypoglycemic effect of oral hypoglycemic agents and mask symptoms of hypoglycaemia. They should be used with caution in patients with spontaneous hypoglycemia or diabetes (particularly labile currents) receiving insulin or oral hypoglycemic agents.
Therapy with beta-blockers may mask the symptoms of hyperthyroidism, abrupt discontinuation of treatment may cause a worsening of the disease.
In the treatment of beta-adrenobloktorami patients with severe atopy or anaphylactic reactions to various allergens may gain a history response when re-exposed to these allergens. Thus epinephrine (adrenaline) in usual doses used for the relief of anaphylactic reactions, can be inefficient.
In rare cases, timolol maleate causes increased muscle weakness in patients with myasthenia gravis or myasthenic symptoms (e.g., diplopia, ptosis, generalized weakness).
In applying means lowering IOP described choroidal detachment after filtration procedures - fistuliziruyuschih operations (trabeculectomy and its modifications with sinusotomy diatermotrabekulospazisom, penetrating deep sclerectomy fistuliziruyuschie and other operations that create a new or existing stimulate the outflow of intraocular fluid path).
Effects on ability to transport management and operation mechanisms
The use of eye drops can cause a transient blurring of vision. While this effect persists, patients should not drive a car or use complex technology.
Symptoms: in addition to ocular irritation and conjunctival hyperemia other undesirable changes in the body of an overdose are not known latanoprost.
Accidental ingestion of latanoprost be appreciated that one vial with 2.5 ml of a solution containing 125 micrograms latanoprost. More than 90% of the drug is metabolized in the "first pass" through the liver. V / IV infusion at a dose of 3 mg / kg in healthy volunteers did not cause any symptoms, but when administered at a dose of 5.5-10 mg / kg were observed nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. These symptoms resolved within 4 hours after stopping the infusion. Patients with moderate bronchial asthma administering latanoprost at a dose of 7 times exceeding the therapeutic one, does not cause bronchospasm.
Symptoms: There are cases of unintentional overdose of timolol maleate eye drops, causing the observed effects similar to those of systemic administration of beta-blockers: dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest.
In the in vitro study, it was shown that when dialysis timolol maleate is easily derived from plasma or whole blood. In patients with renal insufficiency timolol maleate dialyzed worse.
Treatment: overdose Ksalakoma symptomatic therapy.
The interaction of the drug Ksalakom В® not been specifically studied with other drugs.
Not recommended simultaneous application with Ksalakomom into other beta-blockers, since it is possible a marked reduction in IOP or enhancing the systemic effects of beta-blockers.
With simultaneous instillation into the eyes of two prostaglandin analogues described paradoxical increase in IOP, so simultaneous use of two or more prostaglandins, their analogs or derivatives not recommended.
With simultaneous application of timolol maleate with epinephrine (adrenaline) is sometimes developed mydriasis.
Possible additive effect with the development of systemic arterial hypotension and / or bradycardia when timolol maleate combination with the following drugs: calcium channel blockers slow, means causing reduction of catecholamines, beta-blockers, antaritmicheskie agents, cardiac glycosides, guanethidine.
It reported strengthening action systemic beta-blockers (e.g., heart rate reduction, depression) while applying isozyme CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine), and timolol.
Beta-blockers can enhance the hypoglycemic effect of antidiabetic agents.
With the sudden cancellation of clonidine there is an increase in blood pressure. This reaction may be increased by concomitant use of beta-blockers.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature of from 2 В° to 8 В° C. Shelf life - 2 years.
After opening, the vial should be stored at temperatures not above 25 В° C and used within 4 weeks.