Dorzolamide Hydrochloride And Timolol Maleate Preservative Free

Description

11 DESCRIPTION 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-6­ methyl-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 (C=1, water) = ~ -17°. 405 nm Its empirical formula is C 10 H 16 N 2 O 4 S 3

What Is Dorzolamide Hydrochloride And Timolol Maleate Preservative Free Used For?

1 INDICATIONS AND USAGE Dorzolamide hydrochloride and timolol maleate ophthalmic solution preservative free is indicated for the reduction of elevated intraocular pressure (IOP) 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 and timolol maleate ophthalmic solution administered twice a day was slightly less than that seen with the concomitant administration of 0.5% timolol administered twice a day and 2% dorzolamide administered three times a day [see Clinical Studies (14.1) ]. Dorzolamide hydrochloride and timolol maleate ophthalmic solution preservative free is a carbonic anhydrase inhibitor with a beta­ adrenergic receptor blocking agent indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers. The IOP-lowering of dorzolamide hydrochloride and timolol maleate ophthalmic solution twice daily was slightly less than that seen with the concomitant administration of 0.5% timolol twice daily, and 2% dorzolamide three times daily. ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION The dose is one drop of dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 preservative free in the affected eye(s) two times daily. ( 2 )

Side Effects (Adverse Reactions)

6 ADVERSE 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 to 15% of patients. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA Inc. at 1-855-839-8195 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 to 15% of patients: conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching. The following adverse reactions were reported in 1 to 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...

Drug Interactions

7 DRUG INTERACTIONS Potential additive effect of oral carbonic anhydrase inhibitor with dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 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 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 preservative free 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. 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 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...

Contraindications

4 CONTRAINDICATIONS Dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 preservative free is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease [see Warnings and Precautions (5.1) ]. 4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Dorzolamide hydrochloride and timolol maleate ophthalmic solution preservative free is contraindicated in patients with sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, and cardiogenic shock [see Warnings and Precautions (5.2) ]. 4.3 Hypersensitivity Dorzolamide hydrochloride and timolol maleate ophthalmic solution preservative free is contraindicated in patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.3) ] .

Pregnancy and Breastfeeding

8.1 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 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 and timolol maleate ophthalmic solution preservative free should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 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 and timolol maleate ophthalmic solution preservative free 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.

Overdosage

10 OVERDOSAGE 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 Adverse Reactions (6) .] A study of patients with renal failure showed that timolol did not dialyze readily.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Dorzolamide Hydrochloride and Timolol Maleate Ophthalmic Solution, USP (Preservative Free) is supplied in a 0.2 mL low density polyethylene single-dose containers in a foil pouch containing 15 low density polyethylene 0.2 mL single-use containers. Pouch label NDC 42571-382-71 Carton of 60 single-use containers NDC 42571-382-73 Carton of 180 single-use containers NDC 42571-382-27 Store dorzolamide hydrochloride and timolol maleate ophthalmic solution preservative free at 20 to 25°C (68 to 77°F). Do not freeze. Store in the original pouch. After the pouch is opened, store the remaining single-use containers in the foil pouch to protect from light. Write down the date you open the foil pouch in the space provided on the pouch. Discard any unused containers 15 days after first opening the pouch.