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Dorzolamide Hydrochloride-Timolol Maleate

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Overview

What is 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: (4)-4-(ethylamino)-5,6-dihydro-6-methyl-4-thieno[2,3-]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride.  Dorzolamide hydrochloride is optically active. The specific rotation is:

[α]      25ºC     (C=1, water) = ~ -17°.         405 nm

Its empirical formula is CHNOS•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-(-butylamino)-3-[(4-morpho-lino-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:

[α]          25ºC          in 1N HCl (C = 5) = -12.2° (-11.7° to -12.5°).            405 nm

Its molecular formula is CHNOS•CHO 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 ophthalmic solution 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 ophthalmic solution contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate). Inactive ingredients are mannitol, hydroxyethyl cellulose, sodium citrate, sodium hydroxide, and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.



What does Dorzolamide Hydrochloride-Timolol Maleate look like?



What are the available doses of Dorzolamide Hydrochloride-Timolol Maleate?

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What should I talk to my health care provider before I take Dorzolamide Hydrochloride-Timolol Maleate?

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How should I use Dorzolamide Hydrochloride-Timolol Maleate?

Dorzolamide hydrochloride-timolol maleate ophthalmic solution 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 ophthalmic solution 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, ).

The dose is one drop of dorzolamide hydrochloride-timolol maleate ophthalmic solution 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, ).


What interacts with Dorzolamide Hydrochloride-Timolol Maleate?

Dorzolamide hydrochloride-timolol maleate ophthalmic solution is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.



What are the warnings of Dorzolamide Hydrochloride-Timolol Maleate?

Renal failure, in some cases resulting in death, has been observed with acyclovir therapy (see and ).  Thrombotic thrombocytopenic purpura/ hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.

Systemic Exposure

Dorzolamide  hydrochloride-timolol maleate ophthalmic solution 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 ). 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

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 ophthalmic solution is contraindicated [see ]) should, in general, not receive beta-blocking agents, including dorzolamide hydrochloride-timolol maleate ophthalmic solution.

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-adrenergically mediated 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.


What are the precautions of Dorzolamide Hydrochloride-Timolol Maleate?

General

Dorzolamide has not been studied in patients with severe renal impairment (CrCl
Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of   dorzolamide hydrochloride-timolol maleate ophthalmic solution. 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, dorzolamide hydrochloride-timolol  maleate ophthalmic solution should be discontinued and the patient evaluated before considering restarting the drug. (See .)

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide hydrochloride-timolol maleate ophthalmic solution has not been studied in patients with acute angle-closure glaucoma.

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. 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. (See PRECAUTIONS, .)

There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing dorzolamide hydrochloride-timolol maleate ophthalmic solution to this group of patients.

Information for Patients

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or  third degree atrioventricular block, or cardiac failure should be advised not to take this product. (See .)

Dorzolamide hydrochloride-timolol maleate ophthalmic solution contains dorzolamide (which is a sulfonamide) and, although administered topically, is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration, including severe skin reactions. Patients should be advised that if serious or unusual reactions or signs of hypersensitivity occur, they should discontinue the use of the product (see ).

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician's advice.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. (See PRECAUTIONS, .)

Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.

Patients should be advised that dorzolamide hydrochloride-timolol maleate ophthalmic solution contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15  minutes following administration of dorzolamide hydrochloride-timolol maleate ophthalmic solution.

Drug Interactions



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)(mouse) cytogenetic assay; (2) chromosomal  aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.

Timolol maleate was devoid of mutagenic potential when tested (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and 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.

Pregnancy

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 ophthalmic solution 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 ophthalmic solution 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.

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.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.


What are the side effects of Dorzolamide Hydrochloride-Timolol Maleate?

Dorzolamide hydrochloride-timolol maleate ophthalmic solution was evaluated for safety in 1035 patients with elevated intraocular pressure treated for open-angle glaucoma or ocular hypertension. Approximately 5% of all patients discontinued therapy with dorzolamide hydrochloride-timolol  maleate ophthalmic solution because of adverse reactions. The most frequently reported adverse events were taste perversion (bitter, sour, or unusual taste) or ocular burning and/or stinging in up to 30% of patients. Conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching were reported between 5-15% of patients. The following adverse events were reported in 1-5% of patients: abdominal pain, back pain, blepharitis, bronchitis, cloudy vision, conjunctival discharge, conjunctival edema, conjunctival follicles, conjunctival injection, conjunctivitis, corneal erosion, corneal staining, cortical lens opacity, cough, dizziness, dryness of eyes, dyspepsia, eye debris, eye discharge, eye pain, eye tearing, eyelid edema, eyelid erythema, eyelid exudate/scales, eyelid pain or discomfort, foreign body sensation, glaucomatous cupping, headache, hypertension, influenza, lens nucleus coloration, lens opacity, nausea, nuclear lens opacity, pharyngitis, post-subcapsular cataract, sinusitis, upper respiratory infection, urinary tract infection, visual field defect, vitreous detachment.

The following adverse events have occurred either at low incidence (
Other adverse reactions that have been reported with the individual components are listed below:

Dorzolamide — Allergic/Hypersensitivity:

Body as a Whole:

Skin/Mucous Membranes:

Special Senses:

Timolol (ocular administration) — Body as a Whole:

Cardiovascular:

Digestive:

Immunologic:

Nervous System/Psychiatric:

Skin:

Hypersensitivity:

Respiratory:

Endocrine:

Special Senses:

Urogenital:

The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Extremity pain, decreased exercise tolerance, weight loss;  Worsening of arterial insufficiency, vasodilatation; Gastrointestinal pain, hepatomegaly, mesenteric arterial thrombosis, ischemic colitis; Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulo-cytosis; Hyperglycemia, hypoglycemia; Pruritus, skin irritation, increased pigmentation, sweating; Arthralgia; Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased  performance on neuropsychometrics;  Rales, bronchial obstruction; Urination difficulties.


What should I look out for while using Dorzolamide Hydrochloride-Timolol Maleate?

Dorzolamide hydrochloride-timolol maleate ophthalmic solution is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

Systemic Exposure

Dorzolamide  hydrochloride-timolol maleate ophthalmic solution 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 ). 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

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 ophthalmic solution is contraindicated [see ]) should, in general, not receive beta-blocking agents, including dorzolamide hydrochloride-timolol maleate ophthalmic solution.

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-adrenergically mediated 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.


What might happen if I take too much Dorzolamide Hydrochloride-Timolol Maleate?

There are no human data available on overdosage with dorzolamide hydrochloride-timolol maleate ophthalmic solution.

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 ).

A study of patients with renal failure showed that timolol did not dialyze readily.


How should I store and handle Dorzolamide Hydrochloride-Timolol Maleate?

Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature].PHARMACIST:A Schedule CII Narcotic.Manufactured for: a Subsidiary of Qualitest PharmaceuticalsHuntsville, AL 358111-800-444-4011 Rev. 08/14Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1Dorzolamide  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 white, opaque, LDPE plastic ophthalmic dispenser with a transparent LDPE dropper and a dark blue HDPE cap labeled as follows:NDC StorageStore dorzolamide hydrochloride-timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.Manufactured for:Lannett Company, Inc.Philadelphia, PA 19136Manufactured by:Wintac LimitedBangalore – 562 123IndiaMfg. Lic. No: KTK/28/289/97 Rev. 08/11, Revision 1


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Clinical Information

Chemical Structure

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Clinical Pharmacology

Dorzolamide hydrochloride-timolol  maleate ophthalmic solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma, by reducing aqueous humor secretion. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage.

Dorzolamide hydrochloride is an inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase 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. Timolol maleate is a beta and beta (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic  sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing)  activity. The combined effect of these two agents administered as dorzolamide hydrochloride-timolol  maleate ophthalmic solution b.i.d. results in additional intraocular pressure reduction compared to either component administered alone, but the reduction is not as much as when dorzolamide t.i.d. and timolol b.i.d. are administered concomitantly (see ).

Non-Clinical Toxicology
Dorzolamide hydrochloride-timolol maleate ophthalmic solution is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

Systemic Exposure

Dorzolamide  hydrochloride-timolol maleate ophthalmic solution 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 ). 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

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 ophthalmic solution is contraindicated [see ]) should, in general, not receive beta-blocking agents, including dorzolamide hydrochloride-timolol maleate ophthalmic solution.

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-adrenergically mediated 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.

Carbonic anhydrase inhibitors:

Acid-base disturbances:

Beta-adrenergic blocking agents:

Calcium antagonists:

Catecholamine-depleting drugs:

Digitalis and calcium antagonists:

CYP2D6 inhibitors:

Clonidine:





Dorzolamide has not been studied in patients with severe renal impairment (CrCl
Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of   dorzolamide hydrochloride-timolol maleate ophthalmic solution. 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, dorzolamide hydrochloride-timolol  maleate ophthalmic solution should be discontinued and the patient evaluated before considering restarting the drug. (See .)

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide hydrochloride-timolol maleate ophthalmic solution has not been studied in patients with acute angle-closure glaucoma.

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. 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. (See PRECAUTIONS, .)

There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing dorzolamide hydrochloride-timolol maleate ophthalmic solution to this group of patients.

Dorzolamide hydrochloride-timolol maleate ophthalmic solution was evaluated for safety in 1035 patients with elevated intraocular pressure treated for open-angle glaucoma or ocular hypertension. Approximately 5% of all patients discontinued therapy with dorzolamide hydrochloride-timolol  maleate ophthalmic solution because of adverse reactions. The most frequently reported adverse events were taste perversion (bitter, sour, or unusual taste) or ocular burning and/or stinging in up to 30% of patients. Conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching were reported between 5-15% of patients. The following adverse events were reported in 1-5% of patients: abdominal pain, back pain, blepharitis, bronchitis, cloudy vision, conjunctival discharge, conjunctival edema, conjunctival follicles, conjunctival injection, conjunctivitis, corneal erosion, corneal staining, cortical lens opacity, cough, dizziness, dryness of eyes, dyspepsia, eye debris, eye discharge, eye pain, eye tearing, eyelid edema, eyelid erythema, eyelid exudate/scales, eyelid pain or discomfort, foreign body sensation, glaucomatous cupping, headache, hypertension, influenza, lens nucleus coloration, lens opacity, nausea, nuclear lens opacity, pharyngitis, post-subcapsular cataract, sinusitis, upper respiratory infection, urinary tract infection, visual field defect, vitreous detachment.

The following adverse events have occurred either at low incidence (
Other adverse reactions that have been reported with the individual components are listed below:

Dorzolamide — Allergic/Hypersensitivity:

Body as a Whole:

Skin/Mucous Membranes:

Special Senses:

Timolol (ocular administration) — Body as a Whole:

Cardiovascular:

Digestive:

Immunologic:

Nervous System/Psychiatric:

Skin:

Hypersensitivity:

Respiratory:

Endocrine:

Special Senses:

Urogenital:

The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic timolol maleate: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Extremity pain, decreased exercise tolerance, weight loss;  Worsening of arterial insufficiency, vasodilatation; Gastrointestinal pain, hepatomegaly, mesenteric arterial thrombosis, ischemic colitis; Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulo-cytosis; Hyperglycemia, hypoglycemia; Pruritus, skin irritation, increased pigmentation, sweating; Arthralgia; Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased  performance on neuropsychometrics;  Rales, bronchial obstruction; Urination difficulties.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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