Timolol 0.25% and 0.5% (eye drops)

International not patented name

Timolol

Pharmacotherapeutic group

Preparations for managing eye diseases. Beta-adrenoblockers.

Preparation composition

Active substance – timolol maleate (calculated for the base) – 2.5 mg/ml or 5.0 mg/ml;

Excipients – sodium phosphate twice-substituted 12-aquaeous, sodium phosphate once-substituted 2-aquaeous, sodium chloride, trilon B, benzalconium chloride, water for injections.

Pharmacologic action

Pharmacodynamics

Timolol is a highly efficient not selective beta-adrenoreceptors blocker. It does not possess internal sympathomymetic and membrane stabilizing activities. Being applied locally in the form of eye drops it reduces both the normal and the increased intraocular pressures thanks to the intraocular fluid secretion reduction. It does not effect the pupil size. The preparation allows to control the intraocular pressure during sleep. The preparation action is evident in 10 – 30 minutes after having been dropped into the conjunctival  cavity. The maximal reduction of the intraocular cavity is observed in 1 – 2 hours and resists for 12 – 24 hours.

Pharmacokinetics

Being applied locally timolol maleate penetrates the cornea. In small quantities the preparation enters the systemic blood flow through its absorption in the conjunctival vessels, the vessels of the nose mucous membrane and of the lacrimal tract. The plasma protein fixation is less than 10%. It penetrates the breast milk, passes through the hematologic barrier and the placental barrier. It is biotransformed in the liver. It is excreted by the kidneys and the intestine being unchanged and in the form of metabolites. The newborns and infants blood plasma active substance concentrations (Cmax) are much higher than the grown-ups blood plasma Cmax concentrations.

Indications for appliance

The preparation is applied in case of chronic open angle glaucoma, secondary glaucoma (uveal, aphactic, posttraumatic); in case of the ophthalmotonus acute increase; as an additional preparation for reducing the intraocular pressure in case of close angle glaucoma (in combination with myotics).

Mode of appliance and dosage regime

The preparation is used in the form of instillations into the lower conjunctival sac of the eye damaged. The therapy is begun with 0.25% solution (1 drop 1 – 2 times/24 hours), in case the effect is not sufficient 0.5% solution is used (1 drop 1 – 2 times/24 hours). When the intraocular pressure normalizes the preparation being applied regularly the dose should be restricted to 1 drop once a day in the morning.

The therapy lasts as rule for a long time. The therapy duration depends on the disease course and is determined by the physician. The preparation appliance break or the dose changing are possible only by the physician’s prescription.

Special warnings

Appliance during pregnancy and lactation: There is no sufficient experience of the preparation appliance during pregnancy, nevertheless it is determined that timolol passes the placental barrier. The preparation may be received during pregnancy when it is prescribed by the physician in case the curative effect expected exceeds the potential risk for the fetus. In case the preparation has been received in short time before the labor the newborns should be under a close observation for several days after birth.

When timolol is received the lachrymal function, the cornea intactness and the visual field should be monitored; the intraocular pressure should be controlled (in 3 – 4 weeks after the therapy has been begun). When the patient wears soft contact lens he should not use eye drops for the conserving substance may penetrate the soft contact lens and effect unfavorably the eye tissues. The rigid contact lens should be removed before dropping the preparation in and put on again not earlier than in 15 minutes.

In case timolol is prescribed for substituting other beta-adrenoblockers the earlier used preparations appliance is stopped and timolol is prescribed on the following day. When the other anti-glaucoma drugs are withdrawn the both preparations should be applied during 1 day (under the intraocular pressure control), than only timolol is to be applied. When the patient’s therapy is changed for timolol the refraction correction may be necessary after the effects caused by the myotics applied earlier. When timolol has been applied for a long time the therapeutic effect may reduce.

When a surgery under a general narcosis is planned timolol should be withdrawn 48 hours before the operation. So that to reduce the preparation absorption after dropping in the eye one should press on the lachrymal canal near the eye internal angle by a finger. In case of the close angle glaucoma the preparation may be applied only in combination with myomimetic drugs. Other preparations are recommended to be instilled not less than 10 minutes before timolol is to be dropped in.

Effect on the capability to drive and to manage mechanisms: The preparation should be applied with care by driver when driving and by persons whose work demands an increased concentration of attention. Within 30 minutes after the preparation appliance it is necessary to refuse from occupying with potentially dangerous activities demanding an increased attention.

Side effects

As a rule the preparation is tolerated well. When the preparation is applied transiting feeling of mist in the eye (lasting for 30 seconds - 5 minutes), of a foreign body in the eye, of burning and itching in the eyes, lacrimation or dryness in the eyes may be observed.

When timolol is applied for a long time the following local reactions may be observed: conjunctivitis, blepharitis, the cornea sensitivity reduction, superficial keratopathy at some points, corneal epithelium edema, eyelid margins inflammation, the visual acuity and refraction changing (very rarely). The preparation appliance may be accompanied by systemic reactions development in some cases, such as bradycardia, bradyarrhythmia, the arterial pressure reduction, atrioventricular blockade, transiting disturbances of cerebral blood circulation; nasal obstruction, dyspnea, bronchospasm, pulmonary insufficiency; headache, dizziness, weakness, depression; cutaneous eruption, pruritus, urticaria.

Contraindications

Individual hypersensitivity to timolol maleate or to any preparation excipient; cornea dystrophic diseases, severe allergic inflammations of the nasal mucous membrane, bronchial asthma (including that in the anamnesis), chronic obstructive diseases of lungs, sinusoidal bradycardia (50/min or less), AV blockade II and III grade, sinoatrial blockade, acute and chronic heart failure, cardiogenic shock, sinus node weakness syndrome, lactation (breast feeding should be arrested for the period of treating), early childish age.

Caution measures

The preparation should applied with a particular care in patients with pulmonary emphysema, not allergic chronic bronchitis, vasomotor rhinitis, Reynaud disease, acidosis, severe cerebro-vascular insufficiency, diabetes mellitus (especially in case of a labile character), hypoglycemia, hyperthyrosis, myasthenia. The preparation is applied with care in senile patients and in children. When timolol is applied in this category of patients a thorough medical control is necessary.

Timolol is applied with care in combination with calcium canals blockers, preparations of foxglove, reserpine as well as when it is prescribed simultaneously with the other preparations from the group of beta-adrenoblockers.

Timolol masks the symptoms (tachycardia) of hypoglycemia on the background of receiving peroral anti-diabetic drugs and insulin, masks the thyrotoxicosis symptoms (sudden withdrawal may provoke a thryrotoxic crisis)

The hypersensitivity reactions pronouncement increase may be observed.

Interactions with other medicinal preparations

When applied locally timolol is compatible with myotic preparations and carboanhydrase inhibitors. Simultaneous appliance of eye drops containing epinephrine may provoke the pupil dilation. The preparation specific action – the intraocular pressure reduction – increases when it is used simultaneously with the eye drops containing epinephrine and pilocarpine. Simultaneous dropping of two preparations from the group of beta-adrenoblockers is not recommended. When beta-adrenoblockers are applied systemically and locally simultaneously the reciprocal increase of side effects pronouncement is possible.

Timolol increases (reciprocally) the probability of disturbances of the heart automatism, conductivity and contractility on the background of amiodarone, sympatholytics, dilthiazem, verapamil, quinidine preparations intake; risk for hypotension and heart function decompensation an the background of calcium antagonists (dihydropiridine derivatives), cardial glicosides, inhalation anesthetics, enhances the myorelaxants action. When applied simultaneously with reserpine a pronounced bradycardia, hypotony may develop. A simultaneous appliance with insulin or oral anti-diabetic preparations may provoke hypoglycemia.

Overdosing

Symptoms: general resorptive effects characteristic for beta-adrenoblockers (dizziness, headache, arrhythmia, bradycardia, bronchospasm, nauses, vomiting) development.

Treatment: immediate washing eyes with water or physiologic solution, when pronounced side effects are observed symptomatic therapy is necessary.