Systemic Exposure Dorzolamide hydrochloride – timolol maleate contains dorzolamide, a sulfonamide, and timolol maleate, a beta-adrenergic blocking agent; and although administered topically, is absorbed systemically.
Therefore, the same types of adverse reactions that are attributable to sulfonamides and/or systemic administration of beta-adrenergic blocking agents may occur with topical administration.
For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate ( see CONTRAINDICATIONS ).
Fatalities have occurred, although rarely, due to 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 readministered irrespective of the route of administration.
If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.
Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.
In Patients Without a History of Cardiac Failure continued depression of the myocardium with betablocking agents over a period of time can, in some cases, lead to cardiac failure.
At the first sign or symptom of cardiac failure, dorzolamide hydrochloride – timolol maleate should be discontinued.
Obstructive Pulmonary Disease Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which dorzolamide hydrochloride – timolol maleate is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta blockingagents, including dorzolamide hydrochloride – timolol maleate.
Major Surgery The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial.
Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta adrenergicallymediated reflex stimuli.
This may augment the risk of general anesthesia in surgical procedures.
Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia.
Difficulty in restarting and maintaining the heartbeat has also been reported.
For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.
Diabetes Mellitus Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents.
Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Thyrotoxicosis Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.
Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.
Drug Interactions Carbonic anhydrase inhibitors: There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and dorzolamide hydrochloride – timolol maleate.
The concomitant administration of dorzolamide hydrochloride – timolol maleate and oral carbonic anhydrase inhibitors is not recommended.
Acid-base disturbances: Although acid-base and electrolyte disturbances were not reported in the clinical trials with dorzolamide hydrochloride ophthalmic solution, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy).
Therefore, the potential for such drug interactions should be considered in patients receiving dorzolamide hydrochloride –timolol maleate.
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and dorzolamide hydrochloride – timolol maleate should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure.
The concomitant use of two topical beta-adrenergic blocking agents is not recommended.
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents, such as dorzolamide hydrochloride – timolol maleate, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension.
In patients with impaired cardiac function, coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a betablocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digital isand calcium antagonists may have additive effects in prolonging atrioventricular conduction time.
CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.
Injectable Epinephrine: ( See PRECAUTIONS, General, Anaphylaxis .) Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose).
Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose.
No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose).
The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class effect of carbonic anhydrase inhibitors in rats.
Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts.
No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year.
In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day(approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose).
Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.
In a lifetime oral study of timolol maleate in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/ kg/day, (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose).
In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day.
An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans.
Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
The following tests for mutagenic potential were negative for dorzolamide: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 μg/mL).
In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 μg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains.
In the assays with tester strain TA100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2.
A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats with either timolol maleate or dorzolamide hydrochloride demonstrated no adverse effect on male or female fertility at doses up to approximately 100 times the systemic exposure following the maximum recommended human ophthalmic dose.
There are no human data available on overdosage with dorzolamide hydrochloride – timolol maleate.
Symptoms consistent with systemic administration of beta-blockers or carbonic anhydrase inhibitors may occur, including electrolyte imbalance, development of an acidotic state, dizziness, headache, shortness of breath, bradycardia, bronchospasm, cardiac arrest and possible central nervous system effects.
Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored ( see also ADVERSE REACTIONS ).
A study of patients with renal failure showed that timolol did not dialyze readily.
Dorzolamide hydrochloride – timolol maleate (dorzolamide hydrochloride-timolol maleate ophthalmic solution) is the combination of a topical carbonic anhydrase inhibitor and a topical beta- adrenergic receptor blocking agent.
Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6- methyl-4H-thieno[2,3-b]thiopyran]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride.
Dorzolamide hydrochloride is optically active.
The speciﬁc rotation is: [a] 25°C (C=1, water) = ~ -17° .405 nm Its empirical formula is C10H16N2O4S3•HCl and its structural formula is: Dorzolamide hydrochloride has a molecular weight of 360.91.
It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
Timolol maleate is described chemically as: (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5- thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt).Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer.The optical rotation of timolol maleate is: [a] 25°C in 1N HCl (C = 5) = -12.2° (-11.7° to -12.5°) .405 nm Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is: Timolol maleate has a molecular weight of 432.50.
It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol.
Timolol maleate is stable at room temperature.
Dorzolamide hydrochloride – timolol maleate is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution.
The pH of the solution is approximately 5.65, and the osmolarity is 242-323 mOsM.
Each mL of dorzolamide hydrochloride – timolol maleate contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate).
Inactive ingredients are sodium citrate, hydroxyethyl cellulose, sodium hydroxide, mannitol, and water for injection.
Benzalkonium chloride 0.0075% is added as a preservative.
Dorzolamide hydrochloride – timolol maleate ophthalmic solution is a clear, colorless to nearly colorless, slightly viscous solution.
Dorzolamide Hydrochloride – Timolol Maleate Ophthalmic Solution is supplied in a 10-mL white, round low-density polyethylene (LPDE) bottle, with a natural LPDE dropper tip, and blue colored high-density polyethylene (HPDE) eyedropper cap.
A white tamper evident overcap is provided.
Dorzolamide hydrochloride – timolol maleate ophthalmic solution is available as follows: NDC 47781-136-34, 10 mL Storage Store dorzolamide hydrochloride – timolol maleate ophthalmic solution at 20-25°C (68-77°F).
[see USP Controlled Room Temperature].
Protect from light.
Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.
INDICATIONS AND USAGE
Dorzolamide hydrochloride – timolol maleate is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers (failed to achieve target IOP determined after multiple measurements over time).
The IOP-lowering of dorzolamide hydrochloride – timolol maleate b.i.d.
was slightly less than that seen with the concomitant administration of 0.5% timolol b.i.d.
and 2.0% dorzolamide t.i.d.
( see CLINICAL PHARMACOLOGY, Clinical Studies ).
Pediatric Use The safety and effectiveness of dorzolamide hydrochloride ophthalmic solution and timolol maleate ophthalmic solution have been established when administered individually in pediatric patients aged 2 years and older.
Use of these drug products in these children is supported by evidence from adequate and well-controlled studies in children and adults.
Safety and efficacy in pediatric patients below the age of 2 years have not been established.
Pregnancy: Teratogenic Effects: Pregnancy: Category C.
Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥2.5 mg/kg/day (31 times the recommended human ophthalmic dose) revealed malformations of the vertebral bodies.
These malformations occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased fetal weights.
No treatment-related malformations were seen at 1.0 mg/kg/day (13 times the recommended human ophthalmic dose).
Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations.
Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring.
Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions.
Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women.
Dorzolamide hydrochloride– timolol maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers It is not known whether dorzolamide is excreted in human milk.
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration.
Because of the potential for serious adverse reactions from dorzolamide hydrochloride – timolol maleate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
DOSAGE AND ADMINISTRATION
The dose is one drop of dorzolamide hydrochloride – timolol maleate in the affected eye(s) two times daily.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart ( see also PRECAUTIONS, Drug Interactions ).