Timoptic-XE

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Change in eyesight, eye pain, or very bad eye irritation.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Very bad dizziness or passing out.
• Very bad headache.
• Slow heartbeat.
• A heartbeat that does not feel normal.
• Chest pain.
• Trouble breathing.
• Muscle weakness.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Burning.
• Stinging.
• Eye irritation.
• Headache.
• Dizziness.
• Signs of a common cold.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Timoptic XE (timolol gel eye drops) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Timoptic XE. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Mechanism of Action

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.

TIMOPTIC-XE, 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 and optic nerve damage.

The precise mechanism of the ocular hypotensive action of TIMOPTIC-XE is not clearly established at this time. Tonography and fluorophotometry studies of TIMOPTIC® (timolol maleate ophthalmic solution) 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.

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.

Pharmacokinetics

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following once daily administration of TIMOPTIC-XE 0.5% in the morning. The mean peak plasma concentration following this morning dose was 0.28 ng/mL.

Clinical Studies

In controlled, double-masked, multicenter clinical studies, comparing TIMOPTIC-XE 0.25% to TIMOPTIC 0.25% and TIMOPTIC-XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC-XE administered once a day was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered twice a day. The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of TIMOPTIC-XE. Repeated observations over a period of six months indicate that the intraocular pressure-lowering effect of TIMOPTIC-XE was consistent. The results from the largest U.S. and international clinical trials comparing TIMOPTIC-XE 0.5% to TIMOPTIC 0.5% are shown in Figure 1.

TIMOPTIC-XE administered once daily had a safety profile similar to that of an equivalent concentration of TIMOPTIC administered twice daily. Due to the physical characteristics of the formulation, there was a higher incidence of transient blurred vision in patients administered TIMOPTIC-XE. A slight reduction in resting heart rate was observed in some patients receiving TIMOPTIC-XE 0.5% (mean reduction 24 hours post-dose 0.8 beats/minute, mean reduction 2 hours post-dose 3.8 beats/minute) [see ADVERSE REACTIONS].

TIMOPTIC-XE has not been studied in patients wearing contact lenses.

General

Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with TIMOPTIC-XE, alternative therapy should be considered.

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 surface [see PRECAUTIONS, Information for Patients].

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol maleate has little or no effect on the pupil. TIMOPTIC-XE should not be used alone in the treatment of angle-closure glaucoma.

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.

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.

Information for Patients

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see PRECAUTIONS, General].

Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.

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.

Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 10 minutes before instilling TIMOPTIC-XE.

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].

Transient blurred vision, generally lasting from 30 seconds to 5 minutes, following instillation, and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.

Drug Interactions

Patients who are receiving a beta-adrenergic blocking agent orally and TIMOPTIC-XE 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.

Caution should be used in the coadministration of beta-adrenergic blocking agents, such as TIMOPTIC-XE, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. In patients with impaired cardiac function, coadministration should be avoided.

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.

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

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.

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.

[See PRECAUTIONS, General, Anaphylaxis]

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.

In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin, which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at oral doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Pregnancy

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 1000 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. TIMOPTIC-XE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from TIMOPTIC-XE 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

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution) is a colorless to nearly colorless, slightly opalescent, and slightly viscous solution.

TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution), 0.25% timolol equivalent, is supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a yellow polypropylene cap as follows:

NDC 24208-814-25, 5 mL in a 7.5 mL capacity bottle.

TIMOPTIC-XE® (timolol maleate ophthalmic gel forming solution), 0.5% timolol equivalent, is supplied in a white low density polyethylene (LDPE) dispenser with a controlled drop tip and a yellow polypropylene cap as follows:

NDC 24208-816-05, 5 mL in a 7.5 mL capacity bottle.

Storage:

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

Distributed by: Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 USA

TIMOPTIC and TIMOPTIC-XE are trademarks of Valeant Pharmaceuticals International, Inc. or its affiliates.

© Bausch & Lomb Incorporated.

Revised: 10/15

9447300

Rx only

STERILE

5 mL

TIMOPTIC-XE®
(Timolol Maleate Ophthalmic

Gel Forming Solution)

0.25%

Timolol Equivalent
(Timolol Maleate 3.4 mg/mL
equivalent to 2.5 mg/mL timolol)

FOR TOPICAL APPLICATION IN THE EYE

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 purposes not listed in this medication guide.

You should not use this medicine if you are allergic to timolol, or if you have:

• asthma or severe chronic obstructive pulmonary disease (COPD);

• certain serious heart conditions, especially "sick sinus syndrome" or 2nd or 3rd degree "AV block";

• severe heart failure; or

• slow heartbeats that have caused you to faint.

To make sure timolol ophthalmic is safe for you, tell your doctor if you have ever had:

• heart disease, a stroke, a blood clot, or circulation problems;

• breathing problems;

• diabetes;

• a thyroid disorder;

• narrow-angle glaucoma;

• allergies; or

• a muscle disorder such as myasthenia gravis.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Timolol ophthalmic can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

Timolol ophthalmic is not approved for use by anyone younger than 2 years old.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dizziness, headache, slow heartbeats, and trouble breathing.