Timolol

S01E - Antiglaucoma preparations and miotics ATC S01EE01 Small molecule approved 1978 Oral Topical Natural product

JFDA label: Xalacom Eye Drops

Mechanism of Action

Antagonist of Beta-1 adrenergic receptor — Beta-1 adrenergic receptor antagonist; Antagonist of Beta-2 adrenergic receptor — Beta-2 adrenergic receptor antagonist

Target	Action	Gene / class
Beta-1 adrenergic receptor efficacy	ANTAGONIST	ADRB1
Beta-2 adrenergic receptor efficacy	ANTAGONIST	ADRB2

Indications

Approved

Cardiovascular Diseases — cardiovascular disease
Glaucoma — glaucoma
Glaucoma, Open-Angle — open-angle glaucoma
Ocular Hypertension — ocular hypertension

Off-label

Exfoliation Syndrome
Hemangioma
Macular Degeneration
Melanoma
Migraine Disorders
Paronychia
Telangiectasia, Hereditary Hemorrhagic
Varicose Ulcer
Wet Macular Degeneration
Wounds and Injuries

Contraindications

Source: openFDA

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. Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Not Known Arrhythmia · Cardiac Arrest · Palpitation · Worsening Of Angina Pectoris

Vascular disorders (3)

Not Known Mesenteric Arterial Thrombosis · Raynaud S Phenomenon · Vasodilatation

Nervous system disorders (2)

Not Known Cerebral Ischemia · Syncope

Hepatobiliary disorders (1)

Not Known Hepatomegaly

Immune system disorders (1)

Not Known Including Anaphylaxis

Metabolism and nutrition disorders (4)

Not Known Hyperglycemia · Hypoglycemia · Masked Symptoms Of Hypoglycemia In Diabetic Patients · Weight Loss

Gastrointestinal disorders (4)

Not Known Abdominal Pain · Digestive Anorexia · Digestive Gastrointestinal Pain · Ischemic Colitis

Skin and subcutaneous tissue disorders (11)

Not Known Alopecia · And Localized And Generalized Rash · Angioedema · Hematologic Nonthrombocytopenic Purpura · Immunologic Systemic Lupus Erythematosus · Increased Pigmentation · Psoriasiform Rash Or Exacerbation Of Psoriasis · Skin Pruritus · Sweating · Thrombocytopenic Purpura · Urticaria

Psychiatric disorders (2)

Not Known Decreased Libido · Nervous System Psychiatric Increase

Ear and labyrinth disorders (1)

Not Known And Tinnitus

Investigations (2)

Not Known Decreased Corneal Sensitivity · Decreased Exercise Tolerance

General disorders and administration site conditions (13)

Not Known Agranu · And Cold Hands And Feet · And Pe · Cardiovascular Worsening Of Arterial Insufficiency · Claudication · Cystoid Macular Edema · Edema · Extremity Pain · Impotence · It Is Not Always Possible To Re · Pseudopemphigoid · Skin Irritation · Special Senses Ptosis

Respiratory, thoracic and mediastinal disorders (2)

Not Known Pulmonary Edema · Urogenital Retroperitoneal Fibrosis

Dosing

Source: openFDA

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.

Warnings & Precautions

Source: openFDA

Warnings & Precautions

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. Although beta-blockers should be avoided in overt congestive heart failure, they can be used, if necessary, with caution in patients with a history of failure who are well compensated, usually with digitalis and diuretics. Both digitalis and timolol maleate slow AV conduction. If cardiac failure persists, therapy with timolol maleate should be withdrawn. 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, patients receiving timolol should be digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, timolol should be withdrawn. Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered timolol maleate, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of one to two weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, timolol maleate administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue timolol maleate therapy abruptly even in patients treated only for hypertension. 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' IS CONTRAINDICATED, see CONTRAINDICATIONS), SHOULD IN GENERAL NOT RECEIVE BETA-BLOCK

Pregnancy & Lactation

Pregnancy

Lactation

Caution Hale L3 RID 1.2%

The manufacturer of Combigan states that it is not recommended for use during lactation, but there is no evidence for this statement.

Chemistry & Properties

Formula	C13H24N4O3S
Molecular weight	316.43 g/mol
IUPAC name	(2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol
CAS	26839-75-8
PubChem CID	33624
InChIKey	`BLJRIMJGRPQVNF-JTQLQIEISA-N`
logP	0.5 (XLogP 1.8)
Polar surface area	79.74 Å²
H-bond acceptors / donors	8 / 2
Drug-likeness (QED)	0.79
Lipinski violations	0

SMILES

CC(C)(C)NC[C@H](O)COc1nsnc1N1CCOCC1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Substrate	—
CYP2D6	Inhibitor	IC₅₀ 11.000000000000007 µM
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aminophylline	major
Ceritinib	major
Dolasetron	major
Dyphylline	major
Epinephrine	major
Fingolimod	major
Formoterol	major
Indacaterol	major
Iobenguane (I-131)	major
Methacholine	major
Olodaterol	major
Orciprenaline	major
Oxtriphylline	major
Pirbuterol	major
Salbutamol	major
Salmeterol	major
Siponimod	major
Terbutaline	major
Theophylline	major
Vilanterol	major
Abiraterone	moderate
Acetohexamide	moderate
Aldesleukin	moderate
Alectinib	moderate
Alimemazine	moderate
Amifostine	moderate
Atropine	moderate
Betamethasone	moderate
Brigatinib	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Bupropion	moderate
Calcium Phosphate	moderate
Calcium acetate	moderate
Calcium carbonate	moderate
Calcium citrate	moderate
Calcium glubionate anhydrous	moderate
Calcium gluconate	moderate
Calcium lactate	moderate

Showing 40 of 100+.

Registered Products (27)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Nyolol ED	Solution 0.5 %	5 ml	The Jordan Drugstore Co	2.010
Apimol 0.25% eye drops	Ophthalmic Solution as maleate 0.25 %	5 ml	Amman Pharmaceutical Indusries	2.100
OPHTAMOLOL 0.25% E/D	Ophthalmic Solution 0.25 %	5 ml	Dar Al Dawa Development and Investment Co Ltd/Jordan	2.100
Timolol E/D	Ophthalmic Solution 0.5 %	5 ml	AL Razi Drug Store	2.190
Apimol 0.5% eye drops	Ophthalmic Solution (as maleate)5 mg/ml	5 ml	Amman Pharmaceutical Indusries	2.280
OPHTAMOLOL 0.50% E/D	Ophthalmic Solution 0.5 %	5 ml	Dar Al Dawa Development and Investment Co Ltd/Jordan	2.280
Cusimolol E/D	Ophthalmic Solution 0.5 %	5 ml	Jarzeem Drug Store	2.340
LATAZ-CO	Injection 5 mg/ml, 50 mcg/ml	2.5 ml	Sun Set Drug Store	3.190
Fotil Eye Drops	Ophthalmic Solution 2 %, 0.5 %	5 ml	THE ARAB DRUG STORE P.S.C	3.660
Fotil Forte Eye Drops	Ophthalmic Solution 4 %, 0.5 %	5 ml	THE ARAB DRUG STORE P.S.C	3.790
Xalacom Eye Drops	Ophthalmic Solution 5 mg, 50 mcg	2.5 ml	Khoury Drug Store	4.190
Optodrop Co	Vial 0.5 %, 2 %	1 vial	Sun Set Drug Store	4.590
Twinzol	Injection 5 mg/ml, 20 mg/ml	5 ml	Nabulsi Drug Store	4.590
Loprostan Eye Drops	Ophthalmic Solution as Maleate 0.50 %, 0.005 %	2.5 ml	Amman Pharmaceutical Indusries	4.780
Twinzol Single Dose Ophthalmic Solution	Ophthalmic Solution 22.26 mg/ml/0.2 ml, 6.83 mg/ml/0.2 ml	(6 strip each of 5 UNT)	Nabulsi Drug Store	4.830
Duotrav	Injection 40 mcg/ml, 5 mg/ml	2.5 ml	The Jordan Drugstore Co	5.840
BRADO Plus Eye Drops	Ophthalmic Solution 0.2 g/100 ml, 0.68 g/100 ml	5 ml	Amman Pharmaceutical Indusries	6.110
COSOPT Ophthalmic Solution	Ophthalmic Solution 0.5 %, 2 %	5 ml	Adatco Drug Store	6.340
Combigan	Solution 0.5 %, 0.2 %	5 ml	Arab Company for Medical & Agricultural Products	6.790
Daromed-T	Solution 0.5 %, 2 %	5 ml	Dar Al Dawa Development and Investment Co Ltd/Jordan	7.430
Xolamol	Solution 0.5 %w/v, (as Hcl ) 2 % w/v	5 ml	شركة مستودع ادوية الايمان	7.960
BeGan Eye Drops	Ophthalmic Solution 0.03 %	3 ml	Amman Pharmaceutical Industries Co	8.660
Azarga	Injection 10 mg/ml, 5 mg/ml	5 ml	The Jordan Drugstore Co	8.830
Apisopt plus Eye Drops	Ophthalmic Solution as maleate 5 mg/ml, as HCL 2 %	5 ml	Amman Pharmaceutical Industries Co	8.960
BeGanol Eye Drops	Ophthalmic Solution 0.03 g/100 ml, 0.68 g/100 ml	3 ml	Amman Pharmaceutical Indusries	9.170
Lumigan Eye Drops	Ophthalmic Solution 0.3 mg/ml	3 ml	Arab Company for Medical & Agricultural Products	9.620
Ganfort	Solution 0.3 mg, 5 mg	3 ml	Arab Company for Medical & Agricultural Products	10.900