DORZOLAMIDE: 3,814 Adverse Event Reports & Safety Profile

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent. Dorzolamide hydrochloride, USP is described chemically as: (4 S - trans )-4-(ethylamino)-5,6-dihydro-6methyl-4 H -thieno[2,3- b ]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is: [α] 25°C 405 nm (C=1, water) = ~ - 17°. Its empirical formula is C 10 H 16 N 2 O 4 S 3

• HCl and its structural formula is: Dorzolamide hydrochloride, USP has a molecular weight of 360.91. It is a white or almost white crystalline powder, which is soluble in water and slightly soluble in methanol and very slightly soluble in anhydrous ethanol. Timolol maleate, USP is described chemically as: (-)-1-( tert -butylamino)-3-[(4-morpholino-1,2,5thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate, USP possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is: [α] 25°C 405 nm in 1N HCl (C=5) = -12.2° (-11.7° to -12.5°). Its molecular formula is C 13 H 24 N 4 O 3 S•C 4 H 4 O 4 and its structural formula is: Timolol maleate, USP has a molecular weight of 432.50. It is a white, or practically white, odorless or practically odorless powder which is soluble in water, in alcohol, and in methanol; sparingly soluble in chloroform and in propylene glycol; insoluble in ether and in cyclohexane. Timolol maleate, USP is stable at room temperature. Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) is supplied as a sterile, clear, colorless to nearly colorless, 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 and timolol maleate ophthalmic solution, USP (preservative free) contains 20 mg dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (6.83 mg timolol maleate). Inactive ingredients are sodium citrate dihydrate, hydroxyethyl cellulose, sodium hydroxide, mannitol, and water for injection. Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP (preservative free) does not contain a preservative.

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AND USAGE Dorzolamide hydrochloride ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Dorzolamide hydrochloride is a carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. ( 1 )

Instructions For Use

Dorzolamide hydrochloride (dor-ZOE-la-mide HYE-droe-KLOR-ide) ophthalmic solution 2% Before using your dorzolamide hydrochloride ophthalmic solution Before using your dorzolamide hydrochloride ophthalmic solution for the first time, make sure the tamper evident ring between the bottle and the cap is unbroken.

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Figure A . Figure A Step 1. Wash your hands.

Step

2. Before opening the bottle for the first time, tear off the tamper evident ring to break the seal.

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Figure B . Figure B Step 3. To open the bottle, unscrew the cap by turning it in the counterclockwise direction. Do not pull the cap directly up and away from the bottle.

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Figure C . Figure C Giving your dorzolamide hydrochloride ophthalmic solution drops Step 4. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and your eye.

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Figure D . Figure D Step 5. Turn your dorzolamide hydrochloride ophthalmic solution bottle upside down and press gently with your thumb or index finger over the middle of the bottle until a single drop is placed in your eye. Do not touch your eye or eyelid with the dropper tip.

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Figure E . Figure E Step 6. If your healthcare provider has told you to use dorzolamide hydrochloride ophthalmic solution drops in both eyes, repeat Steps 4 and 5. After using your dorzolamide hydrochloride ophthalmic solution Step 7. Replace the cap by turning it clockwise direction until tight.

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Figure F . Figure F After you have used all of your dorzolamide hydrochloride ophthalmic solution doses, there will be some dorzolamide hydrochloride ophthalmic solution medicine left in the dispenser. Do not try to remove the extra medicine from the dorzolamide hydrochloride ophthalmic solution dispenser. Throw away your dorzolamide hydrochloride ophthalmic solution dispenser in your household trash. How should I store dorzolamide hydrochloride ophthalmic solution? Store dorzolamide hydrochloride ophthalmic solution between 68°F to 77°F (20°C to 25°C) Protect from light. After opening, dorzolamide hydrochloride ophthalmic solution can be used until the expiration date on the bottle. Safely throw away medicine that is out of date or no longer needed. Keep dorzolamide hydrochloride ophthalmic solution and all medicines out of the reach of children. Important information about using dorzolamide hydrochloride ophthalmic solution If you have any eye or skin reactions, especially conjunctivitis or eyelid reactions to dorzolamide hydrochloride ophthalmic solution, stop using it and call your doctor right away. If you have eye surgery or have a problem such as trauma or infection of your eye while using dorzolamide hydrochloride ophthalmic solution, call your doctor right away. If you do not handle eye medicines the right way the medicine can become contaminated. If the tip of the dispenser touches your eye or areas around your eye, the tip can become contaminated with bacteria which can cause an eye infection and other serious problems including loss of eyesight. If you use other eye medicines dropped onto the eye like dorzolamide hydrochloride ophthalmic solution, use the medicines at least 5 minutes before or after you use dorzolamide hydrochloride ophthalmic solution. Dorzolamide hydrochloride ophthalmic solution contains benzalkonium chloride which may be absorbed by soft contact lenses. If you wear contact lenses, remove them before you use your dorzolamide hydrochloride ophthalmic solution. You can place your contact lenses back into your eyes 15 minutes after using your dorzolamide hydrochloride ophthalmic solution. ______________________________________________________________________________________________________________________________________________________________ This Instructions for Use has been approved by the U.S. Food and Drug Administration. Dorzolamide hydrochloride ophthalmic solution Figure A Dorzolamide hydrochloride ophthalmic solution Figure B Dorzolamide hydrochloride ophthalmic solution Figure C Dorzolamide hydrochloride ophthalmic solution Figure D Dorzolamide hydrochloride ophthalmic solution Figure E Dorzolamide hydrochloride ophthalmic solution Figure F

AND ADMINISTRATION The dose is one drop of Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) 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 five minutes apart [see Drug Interactions (7.3) ]. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. The dose is one drop of Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) in the affected eye(s) two times daily. ( 2 )

Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients with: Bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease. ( 4.1 ) Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock. ( 4.2 ) Hypersensitivity to any component of this product. ( 4.3 , 5.3 )

4.1 Asthma, COPD Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients with sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, and cardiogenic shock <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

4.3 Hypersensitivity Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is contraindicated in patients who are hypersensitive to any component of this product <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>.

REACTIONS The most frequently reported adverse reactions 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. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Dorzolamide

Hydrochloride and Timolol Maleate Ophthalmic Solution and Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution ( Preservative Free) Dorzolamide hydrochloride and timolol maleate ophthalmic solution and dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) were evaluated in patients with elevated intraocular pressure treated for open-angle glaucoma or ocular hypertension for up to 15 months.

Approximately

5% of all patients discontinued therapy because of adverse reactions. The most frequently reported adverse reactions occurring in up to 30% of patients were taste perversion (bitter, sour, or unusual taste) or ocular burning and/or stinging. The following adverse reactions were reported in 5-15% of patients: conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching. The following adverse reactions 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. Other adverse reactions that have been reported with the individual components are listed below: Dorzolamide 2% Angioedema, asthenia/fatigue, bronchospasm, contact dermatitis, epistaxis, eyelid crusting, ocular discomfort, photophobia, signs and symptoms of ocular allergic reaction, transient myopia. Timolol (ocular administration) Body as a Whole : Asthenia/fatigue; Cardiovascular : Arrhythmia, syncope, cerebral ischemia, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud's phenomenon, and cold hands and feet ; Digestive : Anorexia; Immunologic: Systemic lupus erythematosus; Nervous System/Psychiatric : Increase in signs and symptoms of myasthenia gravis, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss; Skin : Alopecia, psoriasiform rash or exacerbation of psoriasis; Hypersensitivity : Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria, and localized and generalized rash; Respiratory : Bronchospasm (predominantly in patients with pre-existing bronchospastic disease); Endocrine : Masked symptoms of hypoglycemia in diabetic patients; Special Senses : Ptosis, decreased corneal sensitivity, cystoid macular edema, visual disturbances including refractive changes and diplopia, pseudopemphigoid, and tinnitus; Urogenital : Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.

6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of dorzolamide hydrochloride and timolol maleate ophthalmic solution or dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: bradycardia, cardiac failure, cerebral vascular accident, chest pain, choroidal detachment following filtration surgery, depression, diarrhea, dry mouth, dyspnea, heart block, hypotension, iridocyclitis, myocardial infarction, nasal congestion, Stevens-Johnson syndrome, toxic epidermal necrolysis, paresthesia, photophobia, respiratory failure, skin rashes, urolithiasis, and vomiting. Timolol (oral administration) The following additional adverse reactions 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: Allergic : Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole : Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular : Worsening of arterial insufficiency, vasodilatation; Digestive : Gastrointestinal pain, hepatomegaly, mesenteric arterial thrombosis, ischemic colitis; Hematologic : Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin : Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal : Arthralgia; Nervous System/Psychiatric : 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; Respiratory : Rales, bronchial obstruction; Urogenital : Urination difficulties.

AND PRECAUTIONS Potentiation of Respiratory Reactions Including Asthma ( 5.1 )

Cardiac

Failure ( 5.2 )

Sulfonamide

Hypersensitivity ( 5.3 )

Obstructive Pulmonary

Disease ( 5.4 )

Increased

Reactivity to Allergens ( 5.5 ) Potentiation of Muscle Weakness ( 5.6 ) Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus ( 5.7 ) Masking of Thyrotoxicosis ( 5.8 ) Renal and Hepatic Impairment ( 5.9 ) Impairment of Beta-Adrenergically Mediated Reflexes During Surgery ( 5.10 )

5.1 Potentiation of Respiratory Reactions Including Asthma Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) contains 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 systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory 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 <span class="opacity-50 text-xs">[see Contraindications (4.1) and Patient Counseling Information (17.1) ]</span>.

5.2 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 and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) should be discontinued <span class="opacity-50 text-xs">[see Contraindications (4.2) and Patient Counseling Information (17.2) ]</span>.

5.3 Sulfonamide Hypersensitivity Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) contains dorzolamide, a sulfonamide; and although administered topically, it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). 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 <span class="opacity-50 text-xs">[see Contraindications (4.3) and Patient Counseling Information (17.3) ]</span>.

5.4 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 and timolol maleate ophthalmic solution (preservative free) is contraindicated) should, in general, not receive beta-blocking agents, including Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) <span class="opacity-50 text-xs">[see Contraindications (4.1) and Patient Counseling Information (17.1) ]</span>.

5.5 Increased Reactivity to Allergens 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.

5.6 Potentiation of Muscle Weakness 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.

5.7 Masking of Hypoglycemic Symptoms in Patients with 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.

5.8 Masking of 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.

5.9 Renal and Hepatic Impairment Dorzolamide has not been studied in patients with severe renal impairment (CrCl &lt;30 mL/min). Because dorzolamide and its metabolite are excreted predominantly by the kidney, Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) is not recommended in such patients. Dorzolamide has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

5.10 Impairment of Beta-Adrenergically Mediated Reflexes During 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 betaadrenergically 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.

5.11 Corneal Endothelium Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) to this group of patients.

INTERACTIONS Potential additive effect of oral carbonic anhydrase inhibitor with Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). ( 7.1 ) Potential acid-base and electrolyte disturbances. ( 7.2 ) Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. ( 7.3 ) Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. ( 7.4 ) Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. ( 7.5 ) Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. ( 7.6 ) CYP2D6 inhibitors may potentiate systemic beta-blockade. ( 7.7 )

7.1 Oral 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 and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free). The concomitant administration of dorzolamide hydrochloride and timolol maleate ophthalmic solution (preservative free) and oral carbonic anhydrase inhibitors is not recommended.

7.2 High-Dose Salicylate Therapy 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 and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free).

7.3 Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free) should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical betaadrenergic blocking agents is not recommended.

7.4 Calcium Antagonists Caution should be used in the coadministration of beta-adrenergic blocking agents, such as Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, 2%/0.5% (preservative free), 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.

7.5 Catecholamine-Depleting Drugs Close observation of the patient is recommended when a beta-blocker 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.

7.6 Digitalis and Calcium Antagonists The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

7.7 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.

7.8 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.