Each mL of eye drop solution contains: Dorzolamide hydrochloride 22.26 mg e.q. to dorzolamide 20 mg and Timolol maleate 6.83 mg equivalent to timolol 5 mg.
Excipients/Inactive Ingredients: Mannitol, Sodium citrate dihydrate, Hydroxy ethylcellulose, Benzalkonium chloride, Sodium hydroxide solution and water for injection.
Pharmacology: Pharmacodynamics: Dorzolamide: Dorzolamide is carbonic anhydrase inhibitors for ophthalmic use. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In human, CA exists as a number of isoenzymes, the most active being CA-II, found primary in red blood cells (RBCs), but also in other tissues. Inhibition of CA in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular pressure (IOP), Dorzolamide reduce elevated IOP by inhibiting CA-II. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.
Timolol: Timolol is a nonselective β-adrenergic blocking agent. Timolol does not have substantial intrinsic sympathomimetic, parasympathomimetic, or local anesthetic activity. Following topical application to the eye, timolol reduces both elevated and normal intraocular pressure (IOP) in patients with or without open-angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces IOP with little or no effect on accommodation or pupillary size. In patients with elevated IOP, timolol reduces mean IOP by about 25-33%. The drug appears to be equally effective in light- and darkcolored eyes.
The exact mechanism by which β-blockers, including timolol, reduce IOP has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. β-adrenergic blocking agents may block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility.
Pharmacokinetics: Dorzolamide: When topically applied, dorzolamide reach the systemic circulation and accumulate in RBCs during chronic dosing as a result of binding to CA-II. Extensive distribution into RBCs yields a long half-life, approximately 3.5 to 4 months. The parent drugs form a single N-desethyl metabolite that inhibit CA-II less potently than the parent drug, but also inhibits CA-I. The metabolite also accumulates in RBCs, where it binds primary to CA-I. Plasma concentrations of parent and metabolite are generally below the assay limit of quantitation. Plasma protein binding is moderate (approximately 33%) for dorzolamide. This agent is primary excreted unchanged in the urine, and the metabolite also is excreted in urine.
Timolol: The degree of systemic absorption of timolol after topical application to the eye has not been fully elucidated; however, some absorption can apparently occur, since adverse systemic effects have occurred following ophthalmic instillation of the drug. Following topical administration of timolol 0.5% solution twice daily to the eye in a limited number of individuals, mean peak plasma concentrations were 0.46 or 0.35 ng/mL following the morning or afternoon dose, respectively. Following topical application to the eye of 0.25 or 0.5% solution of the drug, reduction in IOP usually occurs within 15-30 minutes, reaches a maximum within 1-5 hours, and persists about 24 hours.
Toxicology: Preclinical safety data: No information.
Treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Children ≥ 2 years and Adults: 1 drop in affected eye(s) twice daily.
Method of Administration: The fixed-combination ophthalmic solution of dorzolamide hydrochloride and timolol maleate should not be administered while wearing soft contact lenses. Contact lenses may be reinserted 15 minutes after a dose of the fixed-combination ophthalmic solution. If the patient is receiving more than one ophthalmic drug, the drug should be administered at least 10 minutes apart.
Dorzolamide: Electrolyte imbalance, development of an acidotic state and possible CNS effect may occur. Monitor serum electrolyte levels (particularly potassium) and blood pH levels. Significant lethality was observed in female rats and mice after single oral dose of 1927 and 1320 mg/kg of dorzolamide, respectively.
Timolol: If ocular overdosage occurs, flush eye(s) with water or normal saline. If accidentally ingested, effort to decrease further absorption may be appropriate (gastric lavage). The most common signs and symptoms of overdosage from systemic β-blocker are bradycardia, hypotension, bronchospasm and acute cardiac failure. If these occur, discontinue therapy and initiate appropriate supportive therapy.
It is contraindicated in patients with: Bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease.
Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock.
Hypersensitivity to any component of this product.
Dorzolamide: Systemic effect: Dorzolamide is sulfonamides and, although administered topically, are absorbed systemically. Therefore, the same types of adverse reactions attributable to systemic sulfonamides may occur with topical administration of this agent. Fatalities have occurred, although rarely, because of severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered regardless of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.
Corneal endothelium effects: Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. The effect of continued administration of dorzolamide on the corneal endothelium has not been fully evaluated.
Acute angle-closure glaucoma: The management of patients with acute angle-closure glaucoma therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide have not been studied in patients with acute angle-closure glaucoma.
Ocular effects: Local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide. Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, discontinue the drug and evaluate the patients before considering restarting the drug.
Concomitant oral carbonic anhydrase inhibitors: There is a potential for an additive effect on the known systemic effects of CA inhibition in patients receiving an oral CA inhibitor and dorzolamide. Concomitant administrative of ophthalmic and oral CA inhibitors is not recommended.
Bacterial keratitis: There have been reports of bacterial keratitis associated with the use of topical ophthalmic products in multiple-dose containers. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.
Contact lenses: The preservative used in this product, benzalkonium chloride, may be absorbed by soft contact lenses. Do not administer these agents while wearing soft contact lenses; reinsert lenses 15 minutes or longer after drug administration.
Timolol: Systemic absorption: It may be absorbed systemically. The same adverse reactions found with systemic β-blockers may occur with topical use. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in asthmatics, and rarely, death associated with cardiac failure, have been reported with topical β-blockers.
Cardiovascular: Timolol may decrease resting and maximal exercise heart rate even in healthy subjects.
Non-allergic bronchospasm: Patients with a history of chronic bronchitis, emphysema, etc, should receive β-blockers with caution; they may block bronchodilation produced by catecholamine stimulation of β2-receptors.
Major surgery: Withdrawing β-blockers before major surgery is controversial. Beta-receptor blockade impairs the heart's ability to respond to β-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia. Some patients on β-blockers have had protracted severe hypotension during anesthesia. Difficulty restarting and maintaining heartbeat has been reported. In elective surgery, gradual withdrawal of β-blockers may be appropriate.
Diabetes mellitus: Administer with caution to patients subject to spontaneous hypoglycemia or to diabetic patients (especially labile diabetics). Beta-blocking agents may mask signs and symptoms of acute hypoglycemia.
Thyroid: Beta-adrenergic blocking agents may mask clinical signs of hyperthyroidism (eg. tachycardia). Manage patients suspected of developing thyrotoxicosis carefully to avoid abrupt withdrawal of β-blockers, which might precipitate thyroid storm.
Cerebrovascular insufficiency: Because of potential effects of β-blockers on blood pressure and pulse, use with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop, consider alternative therapy.
Angle-closure glaucoma: The immediate objective is to reopen the angle, requiring constriction of the pupil with a miotic. These agents have little or no effect on the pupil. When they are used to reduce elevated IOP in angle-closure glaucoma, use with miotic.
Muscle weakness: Beta-blockade may potentiate muscle weakness consistent with certain myasthenic symptoms (eg. diplopia, ptosis, generalized weakness). Timolol has increased muscle weakness in some patients with myasthenic symptoms or myasthenia gravis.
Long-term therapy: In long-term studies (2 and 3 years), no significant difference in mean IOP were observed after initial stabilization.
Effects on ability to drive and use machine: No information.
Use in Children: Safety and efficacy in children have not been established.
Use in Elderly: Dorzolamide: Of all the patients in dorzolamide clinical studies, 44% were 65 years of age or older, and 10% were 75 years of age or older. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals to the product cannot be ruled out.
Timolol: Safety and efficacy were similar in patients 65 years of age or older compared with younger patients, however, the possibility that some older patients may exhibit increased sensitivity to the preparation cannot be ruled out.
Use in Pregnancy: Category C.
Dorzolamide: Maternal toxicity and significant increase in the number of fetal variations (eg. malformations of the vertebral bodies) was seen in animals at dose greater than 20 times the recommended human ophthalmic dose. These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights. There are no adequate and well controlled studies in pregnant woman. Use during pregnancy only if the potential benefit justifies the risk to the fetus.
Timolol: There are no adequate and controlled studies to date using timolol ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Use in Lactation: Dorzolamide: In lactating rats, decreases in body weight gain were seen in offspring with these agents at oral doses greater than 94 times the recommended human ophthalmic dose. A slight delay in postnatal development (incisor eruption, vaginal canalization, and eye openings), secondary to lower fetal body weight, also was noted with dorzolamide. It is not known whether this drug is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Timolol: Timolol is distributed into milk following oral or ophthalmic administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Ocular burning, stinging or discomfort immediately following administration (approximately 33%); bitter taste following administration (approximate 25%); superficial punctate keratitis (10% to 15%); signs and symptoms of ocular allergic reaction (approximately 10%); blurred vision, tearing, dryness, photophobia (approximately 1% to 5%); headache, nausea, asthenia/fatigue (infrequent); skin rashes, urolithiasis, iridocyclitis (rare).
Bradycardia; arrhythmia; hypotension; syncope; heart block; cerebral vascular accident; cerebral ischemia; heart failure; palpitation; cardiac arrest.
Dizziness; depression; fatigue; lethargy; hallucinations; confusion.
Ocular irritation including conjunctivitis; blepharitis; keratitis; blepharoptosis; decreased corneal sensitivity; visual disturbances including refractive changes; diplopia; ptosis.
Bronchospasm (mainly in patients with preexisting bronchospastic disease); respiratory failure; dyspnea.
Aggravation of myasthenia gravis; alopecia; nausea; localized and generalized rash; urticarial; impotence; decreased libido; masked symptoms of hypoglycemia in diabetics; diarrhea.
Dorzolamide: Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide, this disturbance has been reported with oral CA inhibitor and have, in some instances, resulted in drug interactions (eg. toxicity associated with high-dose salicylate therapy). Therefore, consider the potential for such drug interactions in patients receiving either of these agents.
Timolol: Systemic β-adrenergic blocking agents: The possibility of an additive effect on IOP and/or systemic β-adrenergic blockade should be considered in patients who are receiving a systemic β-adrenergic blocking agent and topical timolol concomitantly.
Catecholamine-depleting drugs: When topical timolol is administered concomitantly with a catecholamine-depleting drug (e.g.reserpine), the patient should be observed closely for possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, and/or postural hypotension.
Other cardiovascular drugs: Concomitant administration of β-adrenergic blocking agent and a calcium-channel blocking agent and a cardiac glycoside may have additive effects on prolonging AV conduction. Because AV conduction disturbances, left ventricular failure, and/or hypotension may occur, caution should be exercised if timolol and a calcium-channel blocking agent are used concomitantly, and such concomitant use should be avoided in patients with impaired cardiac function. Severe bradycardia (e.g., 36 bpm), which was associated with a wandering pacemaker in one patients, and transient asystole have been reported when ophthalmic timolol and oral verapamil were used concomitantly. A single IV dose of atropine was effective in managing serious bradycardia in at least one patient. Verapamil should be used with extreme caution in patients receiving ophthalmic timolol; when therapy with a calcium-channel blocking agent is indicated (e.g. for angina) in such patients, an agent with minimal effects on SA node and cardiac conduction (e.g. nifedipine) should be used if possible.
Sinus bradycardia, which recurred upon rechallenge, has been reported when ophthalmic timolol and oral quinidine were used concomitantly. This interaction has been attributed to inhibition of timolol metabolism (via the cytochrome P-450 [CYP] 2D6 isoenzyme) by quinidine.
Usage Instructions: 1. Before using this medicine for the first time, make sure the safety strip on the front of the bottle is intact. There is a small gap between the bottle and the cap in an unopened bottle.
2. After tearing off the safety strip the cap can be removed.
3. To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. The cap must not be pulled directly up and away from the bottle. Pulling the cap directly up would prevent your dispenser from operating properly.
4. The patient must tilt the head back and pull the lower eyelid down slightly to form a "pocket" between the eyelid and the eye.
5. The bottle should be inverted and pressed lightly with the thumb or index finger until a single drop is dispensed into the eye. THE DROPPER TIP MUST NOT TOUCH THE EYE OR EYELID. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.
6. If drop dispensing is difficult for the patient after opening for the first time, the patient should replace the cap on the bottle, tighten it and then remove it by turning the cap in the opposite direction as indicated by the arrows on the top of the cap.
7. If necessary, repeat steps 4 and 5 with the other eye.
8. The cap should be replaced and bottle should be closed securely immediately after use. The arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label for proper closure. The cap must not be tightened excessively because the bottle and cap may get damaged.
9. The dispenser tip is designed to provide a single drop, therefore the hole of the dispenser tip MUST NOT BE ENLARGED.
10. After dispensing all doses, a small amount of the medicine will remain in the bottle. Patient should be instructed not to remove the excess medicine from the bottle.
Incompatibilities: No information.
S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.