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Dozypress-T (Ophthalmic Solution)

COMPOSITION

Each ml contains:
Dorzolamide HCL U.S.P. equivalent to Dorzolamide…………………….20mg
Timolol maleate U.S.P. equivalent to…………………………………………….5mg
With:Benzalkonium chloride 0.0075% (as preservative), hydroxypropyl methylcellulose, sodium citrate, mannitol and purified water.

DESCRIPTION

Dorzolamide hydrochloride-timolol maleate ophthalmic solution is the combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent. Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5, 6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide   7,7-dioxide monohydrochloride. Its empirical formula is C10H16N204S3• HCl and has a molecular weight of 360.91. 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). Its molecular formula is C13H24N4O3S•C4H4O4 and has a molecular weight of 432.50.

CLINICAL PHARMACOLOGY

Mechanism of action:

DOZYPRESS-T EYE are 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 Eye Drops b.i.d. results in additional intraocular pressure reduction compared to either component administered alone.


Pharmacokinetics/Pharmacodynamics
:


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 b.i.d. closely approximates the amount of drug delivered by topical ocular administration of dorzolamide 2% t.i.d. 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.


Timolol Maleate:
 In a study of plasma drug concentrations in six subjects, the systemic exposure to timolol wasdetermined 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.

INDICATIONS & USAGE

DOZYPRESS-T EYE Drops are 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 and Timolol maleate Eye Drops 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.

CONTRAINDICATIONS

Dozypress-T Eye Drops are contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure; (7) cardiogenic shock; or(8) hypersensitivity to any component of this product.

PRECAUTIONS

General: Dorzolamide has not been studied in patients with severe renal impairment (CrCl <30 mL/min).Because dorzolamide and its metabolite are excreted predominantly by the kidney, Dorzolamide hydrochloride and Timolol maleate Eye Drops are 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. 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.Dorzolamide hydrochloride and Timolol maleate Eye Drops 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 and Timolol maleate Eye Drops 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 ageof 2 years have not been established. Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

ADVERSE REACTION

Dorzolamide hydrochloride and Timolol maleate Eye Drops were 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 and Timolol maleate Eye Drops  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.

OVER DOSAGE

There are no human data available on overdosage with Dorzolamide hydrochloride and Timolol maleate Eye Drops. 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.

DOSAGE AND ADMINISTRATION

Instill one drop in affected eye(s) twice daily or as directed by the Ophthalmologist. If more than one topical ophthalmic drug is being used, the drugs should be administrated at least ten minutes apart.

HOW SUPPLIED

DOZYPRESS –T Eye Drops are available as a sterile ophthalmic solution 5ml in pilfer plastic dropper  bottles(Gamma irradiated).

STORAGE

Protect from sunlight and heat. Keep away from children’s reach. Do not freeze. Store between 15˚C-30˚C.
After opening the bottle, use within 4 weeks.