Timolol Maleate Ophthalmic Solution

There have been reports of inadvertent overdosage with Istalol® 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. 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.

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 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 of 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, TIMOPTIC 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 TIMOPTIC is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including TIMOPTIC.

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 betaadrenergically 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 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.

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.

Timolol maleate 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:

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 is stable at room temperature.

Timolol maleate ophthalmic solution is supplied in two formulations: Ophthalmic Solution TIMOPTIC* (timolol maleate ophthalmic solution), which contains the preservative benzalkonium chloride; and Ophthalmic Solution TIMOPTIC* (timolol maleate ophthalmic solution), the preservative-free formulation.

Preservative-free Ophthalmic Solution TIMOPTIC is supplied in OCUDOSE*, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each mL of Preservative-free TIMOPTIC in OCUDOSE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). The pH of the solution is approximately 7.0, and the osmolarity is 252-328 mOsm. Each mL of Preservative-free TIMOPTIC in OCUDOSE 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection.

Patients should be instructed about the use of Preservative-free TIMOPTIC in OCUDOSE.

Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product. (See CONTRAINDICATIONS.)

Timolol is a beta-blocker that also reduces pressure inside the eye.

Timolol ophthalmic (for the eyes) is used to treat open-angle glaucoma and other causes of high pressure inside the eye.

Timolol ophthalmic may also be used for other purposes not listed in this medication guide.

Do not allow the dropper to touch any surface, including the eyes or hands. If the dropper becomes contaminated it could cause an infection in your eye, which can lead to vision loss or serious damage to the eye.

Do not use any other eye medication unless your doctor has prescribed it for you. If you use another eye medication, use it at least 10 minutes before or after using timolol ophthalmic. Do not use the medications at the same time.

Timolol ophthalmic can cause blurred vision. Be careful if you drive or do anything that requires you to be able to see clearly.

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

Do not use this medication if you are allergic to timolol, or if you have:

• asthma or severe chronic obstructive pulmonary disease (COPD);
• certain serious heart conditions, especially "AV block"; or
• severe or uncontrolled congestive heart failure.

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use this medication:

• breathing problems such as bronchitis or emphysema;
• a history of heart disease or congestive heart failure;
• diabetes;
• history of stroke, blood clot, or circulation problems;
• a thyroid disorder;
• a muscle disorder such as myasthenia gravis;
• kidney disease; or
• liver disease.

FDA pregnancy category C. It is not known whether timolol ophthalmic is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

Timolol ophthalmic passes into breast milk and could cause harm to a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not use this medicine for a child younger than 2 years old.

Your pharmacist can provide more information about timolol ophthalmic.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients).

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

Body As A Whole

Headache, asthenia/fatigue, and chest pain.

Cardiovascular

Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular 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

Dizziness, 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, and localized and generalized rash.

Respiratory

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

Endocrine

Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS).

Special Senses

Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing, 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.

Read the entire FDA prescribing information for Timoptic in Ocudose (Timolol Maleate Ophthalmic Solution)