TIMOLOL MALEATE（马来酸噻吗洛尔）
本品主要成分及其化学名称为：主要成分是马来酸噻吗洛尔，其化学名为：（一）-1-（叔丁氨基）-3-［（4-吗啉基-1，2，5-噻二唑-3-基）氧］-2-丙醇顺丁稀二酸盐。
C13H24N4O3S·C4H4O4，
分子量：432.49
性状：本品为无色的澄明液体。
适应症：对原发性开角型青光眼具有良好的降低眼内压疗效。对于某些继发性青光眼，高眼压症，部分原发性闭角型青光眼以及其他药物及手术无效的青光眼，加用本品滴眼可进一—步增强降眼压效果。
用法用量：
滴眼，一次1滴，一日1—2次，如眼压已控制，可改为一日1次。如原用其他药物，住改用本品治疗时．原药物不宜突然停用，应自滴用本品的第二天起逐渐停用
禁忌：
1．支气管哮喘者或有支气管哮喘史者，严重慢性阻塞性肺部疾病。
2．窦性心动过缓，II或III度房室传导阻滞，明显心衰，心源性休克。
3．对本品过敏者。
注意事项：
1．当出现呼吸急促、脉搏明显减慢、过敏等症状时，请立即停止使用本品。
2．使用中若出现脑供血不足症状时应立即停药，
3．心功能损害者，使用本品时应避免服用钙离子拮抗剂．
4．对无心衰史的患者，如出现心衰症状应立即停药。
5.正在服用儿茶酚胺耗竭药(如利血平)者，使用本品时应严密观察。
6．冠状动脉疾患、糖尿病、甲状腺功能亢进和重症肌无力患者，用本品滴眼时需遵医嘱。
7．本品慎用于自发性低血糖患者及接受胰岛素或口服降糖药治疗的患者，因p受体阻滞剂可掩盖低血糖症状。
8．本品不宜单独用于治疗闭角型青光眼。
9．与其他滴眼液联合使用时，请间隔lO分钟以上。
10．定期复查眼压，根据眼压变化调整用药方案
11．用前应摇匀，避免容器尖端接触眼睛，防止滴眼液污染。[孕妇及哺乳期妇女用药]本品对于孕妇的安全性尚未确定。滴眼后可在哺乳期妇女乳汁中测到本品，因对授乳婴儿具有多种潜在不良反应．需根据滴用本品对母亲的重要性决定终止哺乳或终止用药，[儿童用药]本品对于儿童的安全性和疗效尚未确定。
药物相互作用：
1．与肾上腺素合用可引起瞳孔扩大。
2．不主张两种局部p受体阻断剂同时应用。
3．本品与钙通道拮抗剂合用应慎重，囚可引起房室传导阻滞，左心室衰竭及低血压。肘心功能受损的患者，应避免两种药合并使用
4．正在服用儿茶酚胺耗竭药(如利血平)者，使用本品时应严密观察，因可引起低血压和明显的心动过缓。
5．本品与洋地黄类和钙通道拮抗剂合用可进一步延长房室传导时间。
6，本品与奎宁丁合用能引起心率减慢等全身p受休阻断的副作用。可能的原因是奎宁丁可抑制P450酶和CYPZD6对噻吗洛尔的代谢作用。
药理作用：
药理作用：马来酸噻吗洛尔是一种非选择性p—肾上腺能受体阻滞剂，没有明显的内源性拟交感活性和局麻作用，对心肌无直接抑制作用。本品为马来酸噻吗洛尔滴眼液．对高眼压患者和正常人均有降低眼内压作用、其降低眼内压的确切机理尚不清楚，眼压描记和房水荧光光度研究提示本品的降眼压作用与减少房水生成有关非临床毒理研究：致癌性：动物实验显示长期大量口服马来酸噻吗洛尔可使雄性大鼠肾卜腺嗜铬细胞瘤，雌性小鼠良性及恶性肺部肿瘤，良性子宫息肉及乳腺痛的发生率明显增高。生殖毒性：动物实验显示大剂量门服马来酸噻吗洛尔，对雄、雌性小鼠的生殖功能均无影响。
孕妇及哺乳期妇女用药：本品对于孕妇的安全性尚未确定。滴眼后可在哺乳期妇女乳汁中测到本品，因对授乳婴儿具有多种潜在不良反应，需根据滴用本品对母亲的重要性决定终止哺乳或终止用药。
儿童用药：本品对于儿童的安全性和疗效尚未确定。
药物相互作用：
1.与肾上腺素合用可引起瞳孔扩大。
2.不主张两种局部β受体阻断剂同时应用。
3.本品与钙通道拮抗剂合用应慎重，因可引起房室传导阻滞，左心室衰竭及低血压。对心功能受损的患者，应避免两种药合并使用。
4.正在服用儿茶酚胺耗竭药（如利血平）者，使用本品时应严密观察，因可引起低血压和明显的心动过缓。
5.本品与洋地黄类和钙通道拮抗剂合用可进一步延长房室传导时间。
6.本品与奎宁丁合用能引起心率减慢等全身β受体阻断的副作用。可能的原因是奎宁丁可抑制P450酶和CYPZD6对噻吗洛尔的代谢作用。
药物过量：
过量应用本品可引起类似全身应用β受体阻断剂的副作用，如头晕，头痛，气短，心动过缓，支气管痉挛及心搏停止。
包装：聚乙烯塑料眼药瓶。
贮藏：遮光，密闭保存。
药物毒理：
药理作用：
马来酸噻吗洛尔是一种非选择性β-肾上腺能受体阻滞剂，没有明显的内源性拟交感活性和局麻作用。对心肌无直接抑制作用。本品为马来酸噻码洛尔滴眼液，对高眼压患者和正常人均有降低眼内压作用。
其降低眼内压的确切机理尚不清楚，眼压描记和房水荧光光度研究提示本品的降眼压作用与减少房水生成有关。 非临床毒理研究：
致癌性：
动物实验显示长期大量口服马来酸噻吗洛尔可使雄性大鼠肾上腺嗜铬细胞瘤，雌牲小鼠良性及恶性肺部肿瘤，良性子宫息肉及乳腺癌的发生率明显增高。
生殖毒性：
动物实验显示大剂量口服马来酸噻吗洛尔，对雄、雌性小鼠的生殖功能均无影响。 
药代动力学：
动物实验显示，用0．5本品对家兔单剂量滴眼，房水和血中的药物峰浓度出现在用药后30分钟，半衰期为1．5小时。全身吸收的马来酸噻吗洛尔在肝内代谢，70％的药物原型随尿排出。对6个接受治疗者的血浆药物浓度测定显示，每日用0．5％本品滴眼2次，早晨滴药后的平均血浆峰浓度为0．46ng／ml，下午滴眼后约为0．35ng/ml.
betimol (timolol)solution 

DESCRIPTION
Betimol® (timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist for ophthalmic use. The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol. Timolol hemihydrate is the levo isomer. Specific rotation is [α]25405nm=-16° (C=10% as the hemihydrate form in 1N HCl).
The molecular formula of timolol is Formula C13H24N4O3S and its structural formula is:
Timolol (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water and freely soluble in ethanol. Timolol hemihydrate is stable at room temperature.
Betimol® is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered aqueous solution.
It is supplied in two dosage strengths, 0.25% and 0.5%.
Each mL of Betimol® 0.25% contains 2.56 mg of timolol hemihydrate equivalent to 2.5 mg timolol.
Each mL of Betimol® 0.5% contains 5.12 mg of timolol hemihydrate equivalent to 5.0 mg timolol.
Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 - 7.5) and water for injection, benzalkonium chloride 0.01% added as preservative.
The osmolality of Betimol® is 260 to 320 mOsmol/kg.
CLINICAL PHARMACOLOGY
Timolol is a non-selective beta-adrenergic antagonist.
It blocks both beta1-and beta2-adrenergic receptors. Timolol does not have significant intrinsic sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant activity.
Timolol, when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP) 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 IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous humor production.
In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway resistance because of unopposed parasympathetic activity.
Pharmacokinetics
When given orally, timolol is well absorbed and undergoes considerable first pass metabolism. Timolol and its metabolites are primarily excreted in the urine. The half-life of timolol in plasma is approximately 4 hours.
Clinical Studies
In two controlled multicenter studies in the U.S., Betimol® 0.25% and 0.5% were compared with respective timolol maleate eyedrops. In these studies, the efficacy and safety profile of Betimol® was similar to that of timolol maleate.
INDICATIONS AND USAGE
Betimol® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
CONTRAINDICATIONS
Betimol® is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia, second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.
WARNINGS
As with other topically applied ophthalmic drugs, Betimol® 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 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 topical administration of beta-adrenergic blocking agents.
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 cardiac 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. Betimol® should be discontinued at the first sign or symptom of cardiac failure.
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 which are contraindications) should in general not receive beta-blocking agents.
Major Surgery: The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a 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 been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents is recommended. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-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 which might precipitate a thyroid storm.
PRECAUTIONS
General
Because of the potential effects of beta-adrenergic blocking agents relative to 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 Betimol®, 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.)
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.
In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting the pupil. Betimol® has no effect on the pupil. Therefore, if timolol is used in angle-closure glaucoma, it should always be combined with a miotic and not used alone.
Anaphylaxis: 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.
The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft contact lenses should wait 5 minutes after instilling Betimol® before they insert their lenses.
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 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 requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart.
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.)
Drug Interactions
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and Betimol® should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade.
Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently.
Catecholamine-depleting drugs: 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 produce vertigo, syncope, or postural hypotension.
Calcium antagonists: Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.
Digitalis and calcium antagonists: The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.
Injectable Epinephrine: (See PRECAUTIONS, General, Anaphylaxis.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity of timolol (as the maleate) has been studied in mice and rats. In a two-year study orally administrated timolol maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose) in male rats caused a significant increase in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not cause any changes.
In a life span study in mice the overall incidence of neoplasms was significantly increased in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Furthermore, significant increases were observed in the incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). For comparison, the maximum recommended human oral dose of timolol maleate is 1 mg/kg/day.
Mutagenic potential of timolol was evaluated in vivo in the micronucleus test and cytogenetic assay and in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames test) high concentrations of timolol maleate (5000 and 10,000 g/plate) statistically significantly increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains tested. However, no consistent dose-response was observed nor did the number of revertants reach the double of the control value, which is regarded as one of the criteria for a positive result in the Ames test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL, respectively.
No adverse effects on male and female fertility were reported in rats at timolol oral doses of up to 150 mg/kg/day (21,000 times the systemic exposure following the maximum recommended human ophthalmic dose).
PREGNANCY
Teratogenic effects
Category C: Teratogenicity of timolol (as the maleate) after oral administration was studied in mice and rabbits. No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose). 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. Betimol® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing mothers
Because of the potential for serious adverse reactions in nursing infants from timolol, 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 efficacy in pediatric patients have not been established.
ADVERSE REACTIONS
The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Betimol® and timolol maleate (approximately one in eight patients).
The following adverse events were associated with use of Betimol® in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Betimol®:
Ocular:
Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection, and headache.
Body As A Whole:
Headache.
The following side effects were reported in frequencies of 1 to 5%:
Ocular:
Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis, blepharitis and cataract.
Body As A Whole:
Allergic reaction, asthenia, common cold and pain in extremities.
Cardiovascular:
Hypertension.
Digestive:
Nausea.
Metabolic/Nutritional:
Peripheral edema.
Nervous System/Psychiatry:
Dizziness and dry mouth.
Respiratory:
Respiratory infection and sinusitis.
In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:
Ocular:
Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes, diplopia and retinal vascular disorder.
Body As A Whole:
Chest pain.
Cardiovascular:
Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure and cardiac arrest.
Digestive:
Diarrhea.
Endocrine:
Masked symptoms of hypoglycemia in insulin dependent diabetics (See WARNINGS).
Nervous System/Psychiatry:
Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.
Respiratory:
Dyspnea, bronchospasm, respiratory failure and nasal congestion.
Skin:
Alopecia, hypersensitivity including localized and generalized rash, urticaria.
OVERDOSAGE
No information is available on overdosage with Betimol®. Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.
DOSAGE AND ADMINISTRATION
Betimol® Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Betimol® in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.
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.
Since in some patients the pressure-lowering response to Betimol® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Betimol®.
Dosages above one drop of 0.5 percent Betimol® 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 pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.
HOW SUPPLIED
Betimol® (timolol ophthalmic solution) is a clear, colorless solution.
Betimol® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:
Betimol® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:
Storage
Store between 15-30°C (59-86°F). Do not freeze. Protect from light.
附件：

201041222295922.pdf

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注：以下产品不同规格和不同价格，购买以咨询为准！
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产地国家: 美国
原产地英文商品名:
BETIMOL 0.5% EYE DROPS 5ml/bottle
原产地英文药品名:
TIMOLOL
中文参考商品译名:
BETIMOL 0.5%滴眼液 5毫升/瓶
中文参考药品译名:
马来酸噻吗洛尔
生产厂家中文参考译名:
SANTEN OY
生产厂家英文名:
SANTEN OY
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产地国家: 美国
原产地英文商品名:
BETIMOL 0.25% EYE DROPS 5ml/bottle
原产地英文药品名:
TIMOLOL
中文参考商品译名:
BETIMOL 0.25%滴眼液 5毫升/瓶
中文参考药品译名:
马来酸噻吗洛尔
生产厂家中文参考译名:
SANTEN OY
生产厂家英文名:
SANTEN OY