Full Prescribing Info
Timolol maleate.
1 ml of Timo-COMOD 0.5% solution contains: Timolol maleate 6.84 mg (corresponds to 5.0 mg of timolol).
Excipients/Inactive Ingredients: Sodium dihydrogen phosphate dihydrate, sodium hydrogen phosphate dodecahydrate, water for injections.
Timo-COMOD 0.5% does not contain any preservatives.
ATC Code: SOTED01.
Pharmacology: Pharmacodynamics: Timolol is a non-selective beta-receptor blocker without intrinsic sympathomimetic activity or local anesthetic (membrane-stabilising) properties. It inhibits β1-receptors, which are localised above all in the heart muscle as well as β2-receptors.
The stimulating effect of catecholamines on the heart is reduced by timolol. In consequence, the neural transmission in the A-V node is decelerated and the systolic discharge is downcasted. The inhibition of β-receptors in the bronchioles leads to an increase of the airway resistance because of a preponderence of the parasympathicus.
Effect on the eye: Timolol eye drops reduce both elevated and normal intraocular pressure. The accurate mechanism of action of timolol by decreasing the intraocular pressure is not known by now. A fluorometric study and tonographic investigations suggest that its effect is based on the decrease in production of aqueous humor. In some studies a better outflow of aqueous humor could be observed.
The onset of pharmacologic effect is rapid, beginning about 20 minutes after local application to the eye. The maximal reduction of intraocular pressure is reached after one to two hours in a significant decrease in intraocular pressure lasts up to 24 hours under the influence of 0.25% or 0.5% timolol eye drops.
As in other agents which lower intraocular pressure, long-term use of timolol leads to tachyphylaxis in some patients. However, in a long-term clinical trial in which 164 patients treated with timolol were studied over 3 years, after intraocular pressures remained stable at their lowered levels.
In contrast to miotics, timolol reduces the intraocular pressure without affecting accommodation or pupil size. This is especially advantageous for cataract patients. If the patients' therapeutic regimen is changed from miotics to timolol, a correction of refraction may be necessary after the miotic activity subsides.
Pharmacokinetics: Aqueous humor levels: In rabbits aqueous humor levels of 461 ng/100 mg at maximum rate were measured 60 min after the application of 1 drop of timolol 1.0% in men aqueous humor levels of timolol 1 and 2 hours after application of 2 drops of timolol 0.5% amounted 150 ng/l00 mg. After 7 hours the level decreased down to 10 ng/100 mg.
Ocular tissue levels: One drop of a 0.25% solution of 14C-marked timolol was applied to a rabbit eye. The maximum radioactivity was detected after 15-60 minutes in various ocular tissues. In cornea nictilating membrane, iris and ciliary body, radioactivities corresponding to between 1 mg and 10 mg timolol per 100 mg of tissue were measured.
Systemic resorption: Experiments show that timolol is absorbed systematically after local application to the eye. In a clinical trial, timolol which is secreted mainly by the kidneys along with its metabolites, was detected in the urine in every patient.
Plasma concentrations: Plasma concentrations of timolol after local application of the recommended clinical dosages are frequently not detectable (<2 ng/mL) after either one-time usage or continuous use for 2 weeks. The maximal plasma concentration measured from a dosage of 2 drops twice daily was 9.6 ng/mL. It occurred 30 to 90 hours after the onset of usage.
In some cases, the use of timolol-containing eye drops in newborns and small children leads to a higher plasma concentration than in adults. A three week old infant, who was treated with a 0.25% timolol-containing eye drop solution at a dosage of one drop twice daily was found to have a timolol plasma concentration of 34 ng/mL.
Toxicology: Preclinical safety data: Acute toxicity: See Overdosage.
Chronic toxicity/Subchronic toxicity: In studies on rabbits for one year and dogs for two years, topically administered timolol maleate caused no side effects on the eye. Even the long term oral administration of high doses of timolol maleate to dogs and rats did not result in side effects except for bradycardia and an increase in the weight of several organs in particular, the heart, kidney and liver.
Mutagenic and carcinogenic properties: Detailed data on mutagenicity are not available; all currently available studies are negative.
During a two year study on rats in which timolol maleate was orally administered at very high doses (300 times higher than the maximal recommended dosage of 1 mg/kg/day for humans), a statistically significant (p<0.05). Increase in the rate of pheochromocytoma of the adrenal gland occurred in male rats. In rats administered with 25 to 100 times the maximal recommended dose for humans these types of changes did not occur. In a study on mice in which timolol was orally administered over their entire lifespan, a statistically significant (p<0.05). Increase in the rate of benign and malignant lung tumors as well as benign uterine polyps (in female mice) occurred with dosage of 500 mg/kg/day. The increases did not occur however with dosages of 5 or 50 mg/kg/day.
Mammary adenocarcinoma rates also increased in the mice receiving very high doses of timolol maleate (500 mg/kg/day). This may be related to an increase in the serum prolactin concentration, which was observed to be increased in the mice receiving 500 mg/kg/day but not in those receiving 5 or 50 mg/kg/day. An increase in the rate of mammary adenocarcinoma in rodents is seen after administration of several substances known to raise serum prolactin concentrations. In adult woman, the oral ingestion of timolol maleate 60 mg which is the maximum recommended oral dose for humans does not raise serum prolactin levels in a clinically significant manner.
Female mice receiving 500 mg/kg/day showed a statistically significant increase in neoplasms.
Toxicity on fertility and pregnancy: Studies on rats showed that the fertility of male and female rats was not adversely affected by doses of timolol up to 150 times greater than the maximum recommended dosage for humans. Experiments investigating the teratogenicity of orally ingested timolol maleate in mice and rabbits showed no evidence of fetal malformations at dosages of up to 50 mg/kg/day. Ossification was sometimes delayed, but this had no observable effect on postnatal development. Dosages of 1000 mg/kg/day in mice (1000 times the maximal recommended dose for humans) resulted in maternal toxicity as well as in increased rates of fetal resorption. Rabbits receiving 100 mg/kg/day showed similar increased resorption rates but no signs of maternal toxicity.
Elevated intraocular pressure (ocular hypertension); chronic open-angle glaucoma; aphakic glaucoma; concomitant therapy in patients with pediatric glaucoma, who are inadequately controlled with other antiglaucoma therapy.
Dosage/Direction for Use
For ocular use.
The usual starting dose is one drop of 0.25% Timolol solution in the affected eye(s) twice daily. If required, the dose can be increased to 1 drop of 0.5% Timolol solution twice daily. Timo-COMOD 0.5% eye drops are instilled into the conjunctival sac and are suitable for long-term therapy.
For a small proportion of patients, 1 drop of 0.1% Timolol solution, twice a day may be satisfactory. If the clinical response is not adequate with 0.1% solution, the dosage should be increased to 1 drop of 0.25% in the affected eye(s) twice daily.
Newborns and infants: Some cases of apnoea in newborns have been reported, which may have been caused by the immaturity of these patients. Application to premature babies and newborns is not recommended because of the possible central nervous effects.
Due to much higher dosages, based on body weight, in newborns and infants, there is a higher chance of systemic side-effects. Therefore, accurate diagnosis is imperative in infants; the patients have to be observed carefully to detect any sign of systemic beta-receptor blockage.
Symptoms of intoxication: Overdosing may lead to severe hypotension, cardiac insufficiency, cardiogenic shock, bradycardia up to cardiac arrest. In addition, respiratory disturbances, bronchial spasms, vomiting, confusion, and generalized cramping may occur.
Treatment of intoxication: In addition to general measures, vital functions have to be checked and corrected, if necessary under intensive care conditions. The following antidotes are suitable: Atropine: 0.5-2 mg as intravenous bolus injection.
Glucagon: Initially 1-10 mg intravenously, afterwards 2-2.5 mg per hour as infusions.
Beta-sympathomimetic drugs, based on body weight and efficacy: Dobutamine, isoprenaline, orciprerialine or epinephrine.
Pacemaker therapy may be indicated in therapy-resistant bradycardia.
Beta-2-sympathomimetic drugs (as aerosol or in case of insufficient activity as injection) or aminophylline, intravenously, can be given in case of bronchial spasm.
In case of convulsion, slow intravenous application of diazepam is recommended.
Timo-COMOD 0.5% is contraindicated in patients with bronchial hyperreactivity; bronchial asthma; severe chronic obstructive pulmonary disease; sinus bradycardia; second and third degree atrio-ventricular block; overt cardiac failure; cardiogenic shock; hypersensitivity to any ingredient of this product; severe allergic rhinitis or nutritional disorders involving the cornea.
Special Precautions
Contact lenses should be removed from the eye before applying the eye drops and reinserted again 15 minutes after application.
Effects on ability to drive and use machines: Timo-COMOD 0.5% may cause blurred vision after application even at normal dosages and with proper use. This can subsequently impair reaction time while driving or operating machinery. This is especially relevant in combination with alcohol.
Use In Pregnancy & Lactation
No well-controlled studies with Timo-COMOD 0.5% in pregnant and breast-feeding women exist. Therefore, the expected benefit has to be balanced precisely against the possible risks.
When Timo-COMOD 0.5% is applied to the mother shortly before delivery, bradycardia, hypoglycemia and respiratory depression in the neonate may occur; there are reports about β-blockage in neonates with other β-blockers. Neonates therefore should be observed carefully for several days after delivery.
Lactation: After ocular administration, timolol is secreted into breast milk and may accumulate to higher concentrations than in the mother's plasma. Although the amount of active ingredient thus received in breast milk is probably of no risk for the newborn, the child should be carefully observed for symptoms of β1-blockade.
Adverse Reactions
For the assessment of side effects the following frequencies of occurrence are defined: Very common: more than 1 of 10 treated patients; Common: more than 1 of 100 treated patients; Uncommon: more than 1 of 1000 treated patients; Rare: more than 1 of 10 000 treated patients; Very rare: 1 or less than 1 of 10 000 treated patients, including single cases.
Eyes: Very rarely, irritations of the eyes, such as conjunctivitis, blepharitis, keratitis, impaired vision, diplopia, ptosis and sensation of dryness of the eyes.
Systemic side-effects: Cardiovascular system: Very rarely, bradycardia, arrhythmia, hypotension, syncopes, atrioventricular block, cerebrovascular insult, cerebral ischemia, heart failure, cardiac arrest and palpitations.
Respiratory system: Very rarely, bronchospasm (especially in patients with existing bronchospastic disease), respiratory insufficiency and dyspnea.
Skin: Very rarely, hypersensitivities, such as local or general exanthemas, urticaria and individual cases alopecia.
Other side-effects: Very rarely, headache, weakness, vomiting, giddiness and depression.
Advice: Like in every treatment of glaucoma, the intraocular pressure as well as the cornea should be examined regularly.
Contact lenses should be removed before before applying the eye drops and should be reinserted 15 minutes after application the earliest.
Drug Interactions
The concomitant application of adrenaline-containing eye drops may cause mydriasis.
Timolol's pharmacologic action of reducing intraocular pressure is enhanced by adrenaline- or pilocarpine-containing eye drops.
The concomitant systemic use of beta-blockers may lead to mutual increase in each drug's pharmacologic activity; intraocular pressure reduction by timolol will be enhanced as well as systemic beta-blocking activity on the cardiovascular system.
Hypotension and bradycardia may be potentiated by the concomitant use of timolol with oral calcium antagonist, digitalis, catecholamine-releasers or beta-blockers.
Caution For Usage
Instructions for use/handling: As general rule, contact of the bottle tip with eye or skin surface should be avoided when applying eye drops.
Incompatibilities: None known.
Store not above 25°C.
Shelf-Life: The duration of stability is 3 years.
With proper care Timo-COMOD 0.5% can be used up to 12 weeks after the bottle has been opened.
MIMS Class
Antiglaucoma Preparations
ATC Classification
S01ED01 - timolol ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.
Ophth soln 0.5% x 10 mL.
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