Label: TIMOLOL MALEATE solution/ drops

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 C 13H 24N 4O 3S•C 4H 4O 4, 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: timolol maleate ophthalmic solution, which contains the preservative benzalkonium chloride; and timolol maleate ophthalmic solution, the preservative-free formulation.

Preservative-free timolol maleate   ophthalmic solution, USP is supplied in a single-dose vial, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in one dosage strength.  The pH of the solution is approximately 6.8 to 7.2, and the osmolarity is 252 to 328 mOsm. Each mL of preservative-free timolol maleate   ophthalmic solution USP, 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients:  dibasic sodium phosphate dodecahydrate, monobasic sodium phosphate (dihydrate), sodium hydroxide to adjust pH, and water for injection.

Mechanism of Action

Timolol maleate  is a beta 1 and  beta 2 (non-selective)  adrenergic receptor blocking  agent that does not  have  significant  intrinsic sympathomimetic, direct  myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

Beta-adrenergic receptor blockade reduces cardiac output  in  both healthy subjects and patients with heart  disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.

Beta-adrenergic receptor blockade  in the bronchi  and  bronchioles results in increased airway resistance from unopposed parasympathetic activity. Such an effect in patients with asthma  or  other bronchospastic conditions  is  potentially  dangerous.

Timolol maleate ophthalmic solution, when applied topically on the eye, has the action  of reducing elevated as well  as  normal  intraocular  pressure,  whether  or  not accompanied by  glaucoma. Elevated intraocular pressure is a major risk factor  in the pathogenesis of  glaucomatous visual field loss. The higher the level  of  intraocular pressure, the greater  the  likelihood  of  glaucomatous  visual  field  loss  and  optic  nerve  damage.

The onset of reduction in intraocular pressure following administration of timolol maleate ophthalmic solution can usually be detected within  one-half hour after a single dose. The maximum effect usually occurs in one to two hours, and  significant lowering of  intraocular pressure can be maintained for periods as  long  as 24  hours  with a single dose. Repeated observations  over a period of  one year indicate that the intraocular pressure-lowering effect of timolol maleate ophthalmic solution is well maintained.

The precise mechanism of the ocular hypotensive action of timolol maleate ophthalmic solution is not  clearly  established at this time. Tonography  and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous  formation. However,  in some studies a slight increase in outflow facility was  also observed.

Pharmacokinetics

In a study of  plasma drug concentration in six subjects, the  systemic exposure to timolol was determined following twice daily administration of timolol maleate   ophthalmic solution 0.5%. The mean peak plasma concentration following  morning  dosing  was  0.46  ng/mL  and  following  afternoon dosing was  0.35  ng/mL.

Clinical Studies

In controlled multiclinic studies  in  patients  with  untreated intraocular pressures of  22 mmHg or greater, timolol maleate ophthalmic solution, 0.25% or 0.5% administered twice a day produced a greater reduction  in  intraocular pressure than 1,  2, 3, or 4%  pilocarpine solution administered four times a day or 0.5,  1, or 2%  epinephrine hydrochloride solution  administered twice a day.

 In these studies, timolol maleate ophthalmic solution was generally well tolerated and  produced  fewer  and  less severe side effects than either pilocarpine or epinephrine. A slight reduction  of resting heart rate in some patients  receiving timolol maleate ophthalmic solution (mean reduction 2.9 beats/minute standard  deviation  10.2)  was  observed.

Preservative-free timolol maleate   ophthalmic solution is indicated in the treatment of elevated intraocular  pressure  in  patients  with  ocular  hypertension  or  open-angle  glaucoma.

Preservative-free timolol maleate   ophthalmic solution may be used when a patient is sensitive to the preservative in timolol maleate ophthalmic solution, benzalkonium chloride, or  when  use  of a preservative-free topical medication  is  advisable.

Preservative-free timolol maleate   ophthalmic solution is contraindicated in patients with (1) bronchial asthma; (2) a history  of  bronchial  asthma; (3) severe  chronic  obstructive pulmonary disease ( see WARNINGS) ; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure  ( see WARNINGS) ; (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 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, preservative-free timolol maleate   ophthalmic 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 solution is contraindicated  ( see CONTRAINDICATIONS))  should, in general, not receive beta-blockers, including preservative-free timolol maleate   ophthalmic 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 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.

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.

To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or  www.fda.gov/medwatch.

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.

Preservative-free timolol maleate   ophthalmic solution is a sterile solution that does not contain a preservative. The solution from one individual  unit is to be used immediately  after opening for administration to one or  both eyes. Since sterility cannot be  guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.

Preservative-free timolol maleate   ophthalmic solution is available in concentration of 0.5%. The usual starting dose is one drop of 0.25% preservative-free timolol maleate   ophthalmic solution in the affected  eye(s)  administered twice a day. Apply  enough  gentle pressure on the individual  container to obtain a single drop of solution. If the clinical response is  not  adequate, the dosage may be  changed to one  drop  of 0.5%  solution  in the affected  eye(s)  administered twice a day.

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

If the intraocular pressure is  maintained at satisfactory levels, the dosage schedule may be changed to one  drop once a day  in the affected  eye(s). Because of  diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is  best determined by measuring the intraocular  pressure  at  different times during the  day.

Dosages above one drop of 0.5% timolol maleate ophthalmic solution twice a day generally  have not been shown to produce  further reduction in intraocular pressure.  If the patient's intraocular  pressure  is still not at a satisfactory level on this regimen, concomitant therapy with other  agent(s) for lowering intraocular  pressure can be instituted taking  into consideration that the preparation(s) used  concomitantly may contain one  or more preservatives. The concomitant use  of two topical beta-adrenergic blocking agents is not recommended  ( see PRECAUTIONS,  Drug Interactions, Beta-adrenergic blocking agents ) .

Preservative-free sterile timolol maleate   ophthalmic solution, USP is a clear, colorless to  light yellow solution.

Preservative-free timolol maleate  ophthalmic solution USP, 0.5% timolol equivalent, is supplied in a single-dose vial, clear low density  polyethylene  unit  dose container.  Each individual  unit contains  0.3 mL of solution, and  is  available  in a foil laminate  overwrapped   pouch  as  follows:

NDC 42571-398-71; 0.3 mL single-dose vials in package of 60.

Storage

Store at room temperature, 15° to 30°C (59° to 86°F). Protect from freezing. Protect from light.

Because evaporation can occur through the unprotected polyethylene  unit  dose container and prolonged  exposure to direct  light can modify the product, the unit dose container should be kept in the  protective foil overwrap and used  within one month after the foil package  has  been  opened.

Manufactured by:
Micro Labs Limited
Bangalore-560099, INDIA.

Manufactured for:
Micro Labs USA, Inc.
Somerset, NJ 08873

Rev. 06/2022

Rx only
Timolol Maleate Ophthalmic Solution, USP 0.5%
Micro Labs Limited

NDC-42571-398-71
Rx only
Timolol Maleate Ophthalmic Solution, USP 0.5%*
10 ×0.3 mL Single-Dose Vials
Micro Labs Limited

NDC-42571-398-71
Rx only
Timolol Maleate Ophthalmic Solution, USP 0.5%*
60 ×0.3 mL Single-Dose Vials
Micro Labs Limited