TIMOLOL

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent.

Dorzolamide hydrochloride 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: [a] 25°C (C=1, water) = ~ -17°. 405nm Its empirical formula is C 10 H 16 N 2 O 4 S 3 •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 C 13 H 24 N 4 O 3 S•C 4 H 4 O 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 and timolol maleate ophthalmic solution, USP is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution.

The pH of the solution is approximately 5.65, and the osmolarity is to 323 mOsM.

Each mL of dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP contains 20 mg dorzolamide (equivalent to 22.26 mg of dorzolamide hydrochloride) and 5 mg timolol (equivalent to 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 timolol1.

The cure for blue is open-angle and other blue species and other causes cause high pressure within the eye.

The following are used with caution in patients with: diabetes, respiratory problems, history of heart disease, thyroid disease or muscle disease, which may require dose modification or certain tests.

Dorzolamide hydrochloride and 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 beta1 and beta2 (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 and timolol maleate ophthalmic solution twice daily results in additional intraocular pressure reduction compared to either component administered alone, but the reduction is not as much as when dorzolamide administered three times daily and timolol twice daily are administered concomitantly. . 12.3 Pharmacokinetics Dorzolamide Hydrochloride When topically applied, dorzolamide reaches the systemic circulation.

To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in RBCs and plasma and carbonic anhydrase inhibition in RBCs were measured.

Dorzolamide accumulates in

RBCs during chronic dosing as a result of binding to CA-II.

The parent drug forms a single

N-desethyl metabolite, which inhibits CA-II less potently than the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15nM).

Dorzolamide binds moderately to plasma proteins (approximately 33%).

Dorzolamide is primarily excreted unchanged in the urine; the metabolite also is excreted in urine.

After dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.

To simulate the systemic exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks.

The oral dose of 2 mg twice daily closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% three times daily.

Steady state was reached within 8 weeks.

The inhibition of

CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration in healthy individuals.

In a study of plasma drug concentrations in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%.

The mean peak plasma concentration following morning dosing was 0.46 ng/mL.

Beta's receptors are discouraged in the buddy-back and thus reduce the release of water solution and thus reduce eye pressure.

Beta's blockers are the first option in blue therapy and eye pressure, and other drugs may be added when pressure needs to be reduced further, which are affordable.

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 to 15% of patients.fda.gov/medwatch. 6.1 Clinical Trials 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 was evaluated in 1,035 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 to15% of patients: conjunctival hyperemia, blurred vision, superficial punctate keratitis or eye itching.

The following adverse reactions were reported in 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, abdominal pain; 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; Musculoskeletal: Myalgia. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of dorzolamide hydrochloride-timolol maleate ophthalmic solution.

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.

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. .

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

Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with: Bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.

Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock.

Hypersensitivity to any component of this product. 4.1 Asthma, COPD Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease. 4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients with sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, and cardiogenic shock. 4.3 Hypersensitivity Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients who are hypersensitive to any component of this product.

& ADMINISTRATION The dose is one drop of dorzolamide hydrochloride and 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 five minutes apart.

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

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP 2%/0.5% is supplied in 10mL a natural, LDPE plastic ophthalmic dispenser with a natural nozzle and a dark blue, tamper-evident cap.

NDC 71921-226-10, 10 mL in a 10 mL capacity bottle.

Store dorzolamide hydrochloride and timolol maleate ophthalmic solution at 20° to 25°C (68° to 77°F) .

Protect from light.

After opening, dorzolamide hydrochloride and timolol maleate ophthalmic solution can be used until the expiration date on the bottle.

Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (37 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 (15 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 1,000 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 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.

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.

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