Timolol Maleate

INDICATIONS AND USAGE Hypertension Timolol maleate tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. Myocardial Infarction Timolol is indicated in patients who have survived the acute phase of myocardial infarction, and are clinically stable, to reduce cardiovascular mortality and the risk of reinfarction. Migraine Timolol is indicated for the prophylaxis of migraine headache.

DOSAGE AND ADMINISTRATION Hypertension The usual initial dosage of timolol maleate is 10 mg twice a day, whether used alone or added to diuretic therapy. Dosage may be increased or decreased depending on heart rate and blood pressure response. The usual total maintenance dosage is 20 to 40 mg per day. Increases in dosage to a maximum of 60 mg per day divided into two doses may be necessary. There should be an interval of at least 7 days between increases in dosages. Timolol maleate tablets may be used with a thiazide diuretic or with other antihypertensive agents. Patients should be observed carefully during initiation of such concomitant therapy. Myocardial Infarction The recommended dosage for long-term prophylactic use in patients who have survived the acute phase of a myocardial infarction is 10 mg given twice daily (see CLINICAL PHARMACOLOGY ). Migraine The usual initial dosage of timolol maleate is 10 mg twice a day. During maintenance therapy the 20 mg daily dosage may be administered as a single dose. Total daily dosage may be increased to a maximum of 30 mg, given in divided doses, or decreased to 10 mg once per day, depending on clinical response and tolerability. If a satisfactory response is not obtained after 6 to 8 weeks use of the maximum daily dosage, therapy with timolol should be discontinued.

CONTRAINDICATIONS Timolol maleate is contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease (see WARNINGS ); sinus bradycardia; second- and third-degree atrioventricular block; overt cardiac failure (see WARNINGS ); cardiogenic shock; hypersensitivity to this product.

ADVERSE REACTIONS Timolol maleate tablets are usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. In a multi-center (12 week) clinical trial comparing timolol maleate and placebo in hypertensive patients, the following adverse reactions were reported spontaneously and considered to be causally related to timolol maleate: Timolol Maleate (n=176) % Placebo (n=168) % BODY AS A WHOLE fatigue/tiredness 3.4 0.6 headache 1.7 1.8 chest pain 0.6 0 asthenia 0.6 0 CARDIOVASCULAR bradycardia 9.1 0 arrhythmia 1.1 0.6 syncope 0.6 0 edema 0.6 1.2 DIGESTIVE dyspepsia 0.6 0.6 nausea 0.6 0 SKIN pruritus 1.1 0 NERVOUS SYSTEM dizziness 2.3 1.2 vertigo 0.6 0 paresthesia 0.6 0 PSYCHIATRIC decreased libido 0.6 0 RESPIRATORY dyspnea 1.7 0.6 bronchial spasm 0.6 0 rales 0.6 0 SPECIAL SENSES eye irritation 1.1 0.6 tinnitus 0.6 0 These data are representative of the incidence of adverse effects that may be observed in properly selected patients treated with timolol maleate, i.e., excluding patients with bronchospastic disease, congestive heart failure or other contraindications to beta-blocker therapy. In patients with migraine the incidence of bradycardia was 5 percent. In a coronary artery disease population studied in the Norwegian multi-center trial (see CLINICAL PHARMACOLOGY), the frequency of the principal adverse reactions and the frequency with which these resulted in discontinuation of therapy in the timolol and placebo groups were: Adverse Reaction* Withdrawal † Timolol (n=945) % Placebo (n=939) % Timolol (n=945) % Placebo (n=939) % Asthenia or Fatigue 5 1 <1 <1 Heart Rate < 40 beats/minute 5 <1 4 <1 Cardiac Failure-Nonfatal 8 7 3 2 Hypotension 3 2 3 1 Pulmonary Edema-Nonfatal 2 <1 <1 <1 Claudication 3 3 1 <1 AV Block 2nd or 3rd Degree <1 <1 <1 <1 Sinoatrial Block <1 <1 <1 <1 Cold Hands and Feet 8 <1 <1 0 Nausea or Digestive Disorders 8 6 1 <1 Dizziness 6 4 1 0 Bronchial Obstruction 2 <1 1 <1 *When an adverse reaction recurred in a patient, it is listed only once. † Only principal reason for withdrawal in each patient is listed. These adverse reactions can also occur in patients treated for hypertension. The following additional adverse effects have been reported in clinical experience with the drug: Body as a Whole: anaphylaxis, extremity pain, decreased exercise tolerance, weight loss, fever; Cardiovascular: cardiac arrest, cardiac failure, cerebral vascular accident, worsening of angina pectoris, worsening of arterial insufficiency, Raynaud's phenomenon, palpitations, vasodilatation; Digestive: gastrointestinal pain, hepatomegaly, vomiting, diarrhea, dyspepsia; Hematologic: nonthrombocytopenic purpura; Endocrine: hyperglycemia, hypoglycemia; Skin: rash, skin irritation, increased pigmentation, sweating, alopecia; Musculoskeletal: arthralgia; Nervous System: local weakness, increase in signs and symptoms of myasthenia gravis; Psychiatric: depression, nightmares, somnolence, insomnia, nervousness, diminished concentration, hallucinations; Respiratory: cough; Special Senses: visual disturbances, diplopia, ptosis, dry eyes; Urogenital: impotence, urination difficulties. There have been reports of retroperitoneal fibrosis in patients receiving timolol maleate and in patients receiving other beta-adrenergic blocking agents. A causal relationship between this condition and therapy with beta-adrenergic blocking agents has not been established. Potential Adverse Effects In addition, a variety of adverse effects not observed in clinical trials with timolol maleate, but reported with other beta-adrenergic blocking agents, should be considered potential adverse effects of timolol. Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Cardiovascular: Intensification of AV block (see CONT …

Drug Interactions Catecholamine-Depleting Drugs Close observation of the patient is recommended when timolol 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 produce vertigo, syncope, or postural hypotension. Non-Steroidal Anti-Inflammatory Drugs Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti-inflammatory drugs has been reported. When using these agents concomitantly, patients should be observed carefully to confirm that the desired therapeutic effect has been obtained. Calcium Antagonists Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, e.g., nifedipine, while left ventricular failure and AV conduction disturbances were more likely to occur with either verapamil or diltiazem. Intravenous calcium antagonists should be used with caution in patients receiving beta-adrenergic blocking agents. Digitalis and Either Diltiazem or Verapamil The concomitant use of beta-adrenergic blocking agents with digitalis and either diltiazem or verapamil may have additive effects in prolonging AV conduction time. Quinidine Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6. Clonidine Beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta-adrenergic blocking agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-adrenergic blocking agents should be delayed for several days after clonidine administration has stopped.

DESCRIPTION Timolol maleate is a nonselective beta-adrenergic receptor blocking agent. The chemical name for timolol maleate is ( S )-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol ( Z )-2-butenedioate (1:1) salt. It possesses an asymmetric carbon atom in its structure and is provided as the levo isomer. Its molecular formula is C 13 H 24 N 4 O 3 S•C 4 H 4 O 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 supplied as tablets containing 5 mg, 10 mg and 20 mg timolol maleate for oral administration. Inactive ingredients are: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium lauryl sulfate, FD&C Blue No. 2 aluminum lake, and D&C Yellow No. 10 aluminum lake. Timolol Maleate Structural Formula

OVERDOSAGE Overdosage has been reported with timolol maleate tablets. A 30 year old female ingested 650 mg of timolol maleate (maximum recommended daily dose - 60 mg) and experienced second- and third-degree heart block. She recovered without treatment but approximately 2 months later developed irregular heart beat, hypertension, dizziness, tinnitus, faintness, increased pulse rate and borderline first degree heart block. The oral LD 50 of the drug is 1190 and 900 mg/kg in female mice and female rats, respectively. An in vitro hemodialysis study, using 14 C 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. The most common signs and symptoms to be expected with overdosage with a beta-adrenergic receptor blocking agent are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. Therapy with timolol should be discontinued and the patient observed closely. The following additional therapeutic measures should be considered: • (1) Gastric lavage • (2) Symptomatic bradycardia: Use atropine sulfate intravenously in a dosage of 0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker may be considered. • (3) Hypotension: Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or norepinephrine. In refractory cases the use of glucagon hydrochloride has been reported to be useful. • (4) Bronchospasm: Use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered. • (5) Acute cardiac failure: Conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases the use of intravenous aminophylline is suggested. This may be followed if necessary by glucagon hydrochloride which has been reported to be useful. • (6) Heart block (second- or third-degree): Use isoproterenol hydrochloride or a transvenous cardiac pacemaker.

HOW SUPPLIED Timolol Maleate Tablets, USP are available containing 5 mg, 10 mg and 20 mg of timolol maleate, USP. The 5 mg tablets are green, round, flat-faced, unscored tablets debossed with M over 55 on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0055-01 bottles of 100 tablets The 10 mg tablets are green, round, flat-faced, scored tablets debossed with M above the score and 221 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0221-01 bottles of 100 tablets The 20 mg tablets are green, capsule-shaped, scored tablets debossed with M to the left of the score and 715 to the right of the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-0715-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Mylan Pharmaceuticals Inc. Morgantown, WV 26505 Revised: 7/2020 TIM:R16