Label: TIMOLOL MALEATE solution, gel forming / drops

Timolol maleate ophthalmic gel forming solution is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-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:

            250

[α]                                in 1.0N HCl (C = 5%) = -12.2° (-11.7° to -12.5°).

            405 nm

Its molecular formula is C13H24N4O3S•C4H4O4 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 ophthalmic gel forming solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths. The pH of the solution is approximately 7.0, and the osmolarity is 260-330 mOsm. Each mL of timolol maleate ophthalmic gel forming solution 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of timolol maleate ophthalmic gel forming solution 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: gellan gum, tromethamine, mannitol, and water for injection. Preservative: benzododecinium bromide 0.012%.

The gel forming solution contains a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of gellan gum, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film, timolol maleate ophthalmic gel forming solution forms a gel that is subsequently removed by the flow of tears.

Timolol maleate ophthalmic gel forming solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Timolol maleate ophthalmic gel forming solution is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease [see WARNINGS, Obstructive Pulmonary Disease]; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure [see WARNINGS, Cardiac Failure]; (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

As with many topically applied ophthalmic drugs, this drug is absorbed systemically.

The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical ophthalmic administration. For example, severe respiratory reactions and cardiac 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].

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, timolol maleate ophthalmic gel forming solution should be discontinued.

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 Timolol maleate ophthalmic gel forming solution is contraindicated [see CONTRAINDICATIONS] should, in general, not receive beta-blockers, including Timolol maleate ophthalmic gel forming solution.

Major 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.

Diabetes Mellilus

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.

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.

In clinical trials, transient blurred vision upon instillation of the drop was reported in approximately one in three patients (lasting from 30 seconds to 5 minutes). Less than 1% of patients discontinued from the studies due to blurred vision.

The frequency of patients reporting burning and stinging upon instillation was comparable between timolol maleate ophthalmic gel forming solution and timolol maleate ophthalmic solution (approximately one in eight patients).

Adverse experiences reported in 1-5% of patients were:

The following additional adverse experiences have been reported with the ocular administration of this or other timolol maleate formulations:

BODY AS A WHOLE

Asthenia/fatigue, and chest pain.

CARDIOVASCULAR

Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebrovascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud's phenomenon, and cold hands and feet.

DIGESTIVE

Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.

IMMUNOLOGIC

Systemic lupus erythematosus.

NERVOUS SYSTEM/PSYCHIATRIC

Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including depression, confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss.

SKIN

Alopecia and psoriasiform rash or exacerbation of psoriasis.

HYPERSENSITIVITY

Signs and symptoms of systemic allergic reactions including anaphylaxis, angioedema, urticaria, localized and generalized rash.

RESPIRATORY

Bronchospasm (predominantly in patients with preexisting bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.

ENDOCRINE

Masked symptoms of hypoglycemia in diabetic patients [see WARNINGS, Diabetes Mellitus].

SPECIAL SENSES Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery [see PRECAUTIONS, General]; and tinnitus.

UROGENITAL

Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.

The following additional adverse effects 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, vomiting, 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.

To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1- 800-417-9175 or FDA at 1-800 -FDA-1088 or www.fda.gov/medwatch

No data are available in regard to human overdosage with or accidental oral ingestion of timolol maleate ophthalmic gel forming solution. There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest [see ADVERSE REACTIONS].

Overdosage has been reported with timolol maleate tablets. A 30-year-old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.

An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.

Patients should be instructed to invert the closed container and shake once before each use. It is not necessary to shake the container more than once. Other topically applied ophthalmic medications should be administered at least 10 minutes before timolol maleate ophthalmic gel forming solution [see PRECAUTIONS, Information for Patients and accompanying INSTRUCTIONS FOR USE]. Timolol maleate ophthalmic gel forming solution is available in concentrations of 0.25% and 0.5%. The dose is one drop of timolol maleate ophthalmic gel forming solution (either 0.25% or 0.5%) in the affected eye(s) once a day.

Because in some patients the pressure-lowering response to timolol maleate ophthalmic gel forming solution may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with timolol maleate ophthalmic gel forming solution.

Dosages higher than one drop of 0.5% timolol maleate ophthalmic gel forming solution once a day have not been studied. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered. The concomitant use of two topical beta-adrenergic blocking agents is not recommended [see PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents]. When patients have been switched from therapy with timolol maleate ophthalmic solution administered twice daily to timolol maleate ophthalmic gel forming solution administered once daily, the ocular hypotensive effect has remained consistent.

Timolol maleate ophthalmic gel forming solution is a colorless to nearly colorless, slightly opalescent and slightly viscous solution free from visible extraneous matter.

Timolol maleate ophthalmic gel forming solution, 0.25% timolol equivalent, is supplied in a natural high density polyethylene (HDPE) plugged with 60 µL Natural low density polyethylene (LDPE) Nozzle and a yellow high density polyethylene (HDPE) cap as follows:

NDC 70069-241-01, 5 mL in a 10 mL capacity bottle.

Timolol maleate ophthalmic gel forming solution, 0.5% timolol equivalent, is supplied in a natural high density polyethylene (HDPE) plugged with 60 µL Natural low density polyethylene (LDPE) Nozzle and a yellow high density polyethylene (HDPE) cap as follows:

NDC 70069-251-01, 5 mL in a 10 mL capacity bottle.

Storage

Store at 15°C to 25°C (59°F to 77°F). Avoid Freezing. Protect from light.

Instructions for Use

Timolol Maleate (tim oh lol mal ee ate) Ophthalmic Gel Forming Solution 0.25% and 0.5 %

Read this Instructions for Use that comes with timolol maleate ophthalmic gel forming solution before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

Important information about timolol maleate ophthalmic gel forming solution:

          Use timolol maleate ophthalmic gel forming solution exactly as your doctor tells you to use it. Your doctor will tell you how much timolol maleate ophthalmic gel forming solution to use and when to use it.

          If you use other medicines in your eye, wait at least 10 minutes between using timolol maleate ophthalmic gel forming solution and your other eye medicines.

           Do not touch your eye or areas around your eye with the tip of the timolol maleate ophthalmic gel forming solution bottle. You may get bacteria on the tip of the bottle that can cause you to get an eye infection that can lead to serious eye damage or vision loss.

How should I use timolol maleate ophthalmic gel forming solution?

Step 1. Wash your hands.

Step 2. Turn your closed bottle of timolol maleate ophthalmic gel forming solution upside down (invert) and shake once.

Step 3. Remove the timolol maleate ophthalmic gel forming solution cap by turning the cap in the direction of the arrows shown (See Figure A). Put the cap in a clean and dry area. Do not let the tip of the bottle touch your fingers or other surfaces.

Step 4. Hold the bottle between your thumb and index finger with 1 hand. Use the index finger of the other hand to pull down the lower eyelid to form a pocket for the eye drop (See Figure B). Tilt your head backwards.

Step 5. Place the tip of the bottle close to your eye. Be careful not to touch your eye with the tip of the bottle. Gently squeeze the bottle and let 1 drop fall into the space between your lower eyelid and your eye (See Figure C). If a drop misses your eye, follow the instructions in steps 4 and 5 again.

Step 6. If your doctor has told you to use timolol maleate ophthalmic gel forming solution in both eyes, repeat steps 4 and 5 for your other eye.

Step 7. Put the cap back on the bottle and close.

                 The timolol maleate ophthalmic gel forming solution bottle tip is made to give 1 drop at a time. Do not try to make the hole in the tip of your bottle bigger.

                 Do not wash the bottle tip.

                 After you have used all of your timolol maleate ophthalmic gel forming solution doses, there will be some timolol maleate ophthalmic gel forming solution left in the bottle. Do not try to remove the extra timolol maleate ophthalmic gel forming solution from the bottle. Throw it away.

How should I store timolol maleate ophthalmic gel forming solution?

     Store timolol maleate ophthalmic gel forming solution at room temperature between 59°F to 77°F (15°C to 25°C) in an upright position.

     Do not freeze timolol maleate ophthalmic gel forming solution.

     Keep timolol maleate ophthalmic gel forming solution out of light.

Keep timolol maleate ophthalmic gel forming and all medicines out of the reach of children.

If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for more information about timolol maleate ophthalmic gel forming solution that is written for health professionals.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Somerset Therapeutics, LLC

Somerset, NJ 08873

Made in India

Code No.: KR/DRUGS/KTK/28/289/97

Revised: October 2024

ST-TGS/P/03

1201010

Timolol Maleate Ophthalmic Gel Forming Solution, 0.25%

Container Label

5 mL

Timolol Maleate 3.4 mg/mL equivalent to 2.5 mg/mL Timolol)

FOR TOPICAL APPLICATION IN THE EYE

Timolol Maleate Ophthalmic Gel Forming Solution, 0.25%

Carton Label

5 mL

Timolol Maleate 3.4 mg/mL equivalent to 2.5 mg/mL Timolol)

FOR TOPICAL APPLICATION IN THE EYE

Timolol Maleate Ophthalmic Gel Forming Solution, 0.5%

Container Label

5 mL

Timolol Maleate 6.8 mg/mL equivalent to 5 mg/mL Timolol)

FOR TOPICAL APPLICATION IN THE EYE

Timolol Maleate Ophthalmic Gel Forming Solution, 0.5%

Carton Label

5 mL

Timolol Maleate 6.8 mg/mL equivalent to 5 mg/mL Timolol)

FOR TOPICAL APPLICATION IN THE EYE