DORZOLAMIDE HYDROCHLORIDE TIMOLOL MALEATE: Package Insert and Label Information

DORZOLAMIDE HYDROCHLORIDE TIMOLOL MALEATE — dorzolamide hydrochloride and timolol maleate solution/ drops
Biocon Pharma Inc.

1 INDICATIONS & USAGE

Dorzolamide hydrochloride and timolol maleate ophthalmic solution, USP 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, USP 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)].

2 DOSAGE & 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 [see Drug Interactions (7.3)].

3 DOSAGE FORMS & STRENGTHS

Ophthalmic solution containing dorzolamide 20 mg/mL (2%) equivalent to 22.26 mg/mL of dorzolamide hydrochloride and timolol 5 mg/mL (0.5%) equivalent to 6.83 mg/mL of timolol maleate.

4 CONTRAINDICATIONS

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 [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

4.3 Hypersensitivity

Dorzolamide hydrochloride and timolol maleate ophthalmic solution is contraindicated in patients who are hypersensitive to any component of this product [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Potentiation of Respiratory Reactions Including Asthma

Dorzolamide hydrochloride and timolol maleate ophthalmic solution 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 [see Contraindications (4.1)].

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 beta-blocking 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 should be discontinued [see Contraindications (4.2)].

5.3 Sulfonamide Hypersensitivity

Dorzolamide hydrochloride and timolol maleate ophthalmic solution 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. 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 [see Contraindications (4.3)].

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 is contraindicated) should, in general, not receive beta-blocking agents, including dorzolamide hydrochloride-timolol maleate ophthalmic solution [see Contraindications (4.1)].

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 <30 mL/min). Because dorzolamide and its metabolite are excreted predominantly by the kidney, dorzolamide hydrochloride-timolol maleate ophthalmic solution 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 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.

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 to this group of patients.

5.12 Bacterial Keratitis

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.

6 ADVERSE REACTIONS

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-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 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, 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.

7 DRUG INTERACTIONS

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. The concomitant administration of dorzolamide hydrochloride and timolol maleate ophthalmic solution 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.

7.3 Beta-Adrenergic Blocking Agents

Patients who are receiving a beta-adrenergic blocking agent orally and dorzolamide hydrochloride-timolol maleate ophthalmic solution 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-timolol maleate ophthalmic solution, 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. 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.

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