英文药名: Neptazane(Methazolamide Tablets)

中文药名: 醋甲唑胺片

药品名称

通用名: 醋甲唑胺片
英文名: METHAZOLAMIDE TABLETS, Neptazane
药品类别: 眼科用药
性状: 本品为白色片
药理毒理

本品化学结构类似乙酰唑胺(在氮原子上多一个甲基)。因此, 药理作用及作用机理与乙酰唑胺相同。又因醋甲唑胺的结构设计减少了电离作用，故眼内透性较乙酰唑胺增强。本品穿透血-房水和血-脑屏障的功能亦较乙酰唑胺强(人脑脊髓液的浓度比乙酰唑胺高50倍)。抑制碳酸酐酶作用比乙酰唑胺强60%, 在体内仅55%的醋甲唑胺与血浆蛋白结合(而90%～95%的乙酰唑胺与血浆蛋白结合)。因为只有药物剂量的未结合部分发挥药理作用，故较低剂量即有明显降眼压反应。醋甲唑胺可抑制房水生成，大部分患者用药后房水生成可减少40%。口服1～2 小时后产生降眼压作用，维持16～18小时。本品的降眼压作用呈剂量依赖性。应用25、50及100mg口服，每8h 1次，可使眼压分别下降3.3、4.3及5.6mmHg。
药代动力学

本品经胃肠道吸收良好，较乙酰唑胺吸收稍慢。血清浓度与剂量呈线性关系。血浆蛋白结合率55%，低于乙酰唑胺(90%)，在血浆pH值范围，39%的醋甲唑胺处于非电离状态。口服100mg后，血清峰值出现在服药后2～3小时，峰浓度约为17μg/ml，峰浓度保持恒定至少8小时。醋甲唑胺的脂溶性和水溶性都比乙酰唑胺，这些特性有助于药物从肾小管重吸收，增加药物的半衰期和血浆浓度。血浆半衰期约14小时，明显长于乙酰唑胺。25%的本品以原型，75%以代谢产物形式经尿排泄。
适应症

用于原发性开角型青光眼、闭角型青光眼及某些继发性青光眼，局部用抗青光眼药眼压控制不理想患者的辅助治疗。因本品降眼压的同时对酸碱平衡影响较少，故对于患有严重阻塞性肺部疾患的患者本品优于乙酰唑胺。醋甲唑胺对尿枸橼酸分泌的影响较乙酰唑胺小，故对于需口服碳酸酐酶抑制剂治疗但又易引起肾结石形成的患者，推荐应用醋甲唑胺。
用法用量

成人口服初始用药时，用25mg，一日2次，这一剂量常可使眼压下降4～ 5mmHg，且副作用最小。如用药后降眼压效果不理想，剂量可加大为50mg，一日 2次。
任何疑问，请遵医嘱！
不良反应

1. 有报道醋甲唑胺可引起严重的血液学不良反应，包括再生障碍性贫血和粒细胞缺乏症。
2. 有报道服醋甲唑胺可引起肾结石，但非常罕见。
3. 其他有恶心、厌食、感觉异常、不适、疲劳及皮肤糜烂等不良反应。
禁忌症

1．肝、肾功能不全致低钠血症、低钾血症、高氯性酸中毒，肾上腺衰竭及肾上腺皮质机能减退(阿狄森病)和有肝昏迷倾向患者禁用。
2．有磺胺过敏史的患者禁用。
注意事项

1．慎用于有代谢性酸中毒及低血钾危险的患者。
2．闭角型青光眼不应用醋甲唑胺代替手术治疗，否则可引起永久性粘连性房角关闭。
3．本品不能长期用于控制眼压。
孕妇及哺乳期妇女用药

1．本品可引起啮齿类动物畸形，孕妇应避免服用。
2．尚不清楚本品否分泌至乳液中，哺乳期妇女若需用本品治疗，应停止哺乳。
儿童用药

本品对儿童的安全性和疗效尚不清楚。
老年患者用药

老年人和成年人对本品有很好的耐受性，故本品适用于老年患者。
药物相互作用

1. 碳酸酐酶抑制剂与高剂量阿斯匹林合用可引起严重的代谢紊乱。因此，本品与水杨酸制剂合用要慎重。
2. 低剂量醋甲唑胺本身不引起低血钾，但碳酸酐酶抑制剂可增加其他药物的排钾作用。
3. 与促肾上腺皮质激素、糖皮质激素联合使用，可以导致严重的低血钾，在联合用药时应注意监护血清钾的浓度及心脏功能。亦应估计到长期同时使用有增加低血钙的危险，可以造成骨质疏松，因为这些药增加钙的排泄。

规格：50mg *100 片

NEPTAZANE (methazolamide tablets) tablet
[Fera Pharmaceuticals]

DESCRIPTION
Methazolamide, a sulfonamide derivative, is a white crystalline powder, weakly acidic, slightly soluble in water, alcohol and acetone. The chemical name for methazolamide is: N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazo1-2(3H)-ylidene]-acetamide and it has the following structural formula:

Each tablet, for oral administration, contains 25 mg or 50 mg methazolamide. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, magnesium stearate (powder), and microcrystalline cellulose.

CLINICAL PHARMACOLOGY

Methazolamide is a potent inhibitor of carbonic anhydrase.

Methazolamide is well absorbed from the gastrointestinal tract. Peak plasma concentrations are observed 1 to 2 hours after dosing. In a multiple-dose, pharmacokinetic study, administration of methazolamide 25 mg bid, 50 mg bid, and 100 mg bid demonstrated a linear relationship between plasma methazolamide levels and methazolamide dose. Peak plasma concentrations (Cmax) for the 25 mg, 50 mg and 100 mg bid regimens were 2.5 mcg/mL, 5.1 mcg/mL, and 10.7 mcg/mL, respectively. The area under the plasma concentration-time curves (AUC) was 1130 mcg.min/mL, 2571 mcg.min/mL, and 5418 mcg.min/mL for the 25 mg, 50 mg, and 100 mg dosage regimens, respectively.

Methazolamide is distributed throughout the body including the plasma, cerebrospinal fluid, aqueous humor of the eye, red blood cells, bile and extra-cellular fluid. The mean apparent volume of distribution (Varea/F) ranges from 17 L to 23 L. Approximately 55% is bound to plasma proteins. The steady-state methazolamide red blood cell:plasma ratio varies with dose and was found to be 27:1, 16:1, and 10:1 following the administration of methazolamide 25 mg bid, 50 mg bid, and 100 mg bid, respectively.

The mean steady-state plasma elimination half-life for methazolamide is approximately 14 hours. At steady-state, approximately 25% of the dose is recovered unchanged in the urine over the dosing interval. Renal clearance accounts for 20% to 25% of the total clearance of drug. After repeated bid-tid dosing, methazolamide accumulates to steady-state concentrations in 7 days.

Methazolamide’s inhibitory action on carbonic anhydrase decreases the secretion of aqueous humor and results in a decrease in intraocular pressure. The onset of the decrease in intraocular pressure generally occurs within 2 to 4 hours, has a peak effect in 6 to 8 hours and a total duration of 10 to 18 hours.

Methazolamide is a sulfonamide derivative; however, it does not have any clinically significant antimicrobial properties. Although methazolamide achieves a high concentration in the cerebrospinal fluid, it is not considered an effective anticonvulsant.

Methazolamide has a weak and transient diuretic effect; therefore, use results in an increase in urinary volume, with excretion of sodium, potassium, and chloride. The drug should not be used as a diuretic. Inhibition of renal bicarbonate reabsorption produces an alkaline urine. Plasma bicarbonate decreases, and a relative, transient metabolic acidosis may occur due to a disequilibrium in carbon dioxide transport in the red cell. Urinary citrate excretion is decreased by approximately 40% after doses of 100 mg every 8 hours. Uric acid output has been shown to decrease 36% in the first 24 hour period.

INDICATIONS AND USAGE

NEPTAZANETM is indicated in the treatment of ocular conditions where lowering intraocular pressure is likely to be of therapeutic benefit, such as chronic open-angle glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where lowering the intraocular pressure is desired before surgery.

CONTRAINDICATIONS

Methazolamide therapy is contraindicated in situations in which sodium and/or potassium serum levels are depressed, in cases of marked kidney or liver disease or dysfunction, in adrenal gland failure, and in hyperchloremic acidosis. In patients with cirrhosis, use may precipitate the development of hepatic encephalopathy.

Long-term administration of methazolamide is contraindicated in patients with angle-closure glaucoma, since organic closure of the angle may occur in spite of lowered intraocular pressure.

WARNINGS

Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Hypersensitivity reactions may recur when a sulfonamide is readministered, irrespective of the route of administration.

If hypersensitivity or other serious reactions occur, the use of this drug should be discontinued.

Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma, and death have been reported with concomitant use of high-dose aspirin and carbonic anhydrase inhibitors.

PRECAUTIONS

General

Potassium excretion is increased initially upon administration of methazolamide and in patients with cirrhosis or hepatic insufficiency could precipitate a hepatic coma.

In patients with pulmonary obstruction or emphysema, where alveolar ventilation may be impaired, methazolamide should be used with caution because it may precipitate or aggravate acidosis.

Information for patients

Adverse reactions common to all sulfonamide derivatives may occur: anaphylaxis, fever, rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, leukopenia, pancytopenia, and agranulocytosis. Precaution is advised for early detection of such reactions, and the drug should be discontinued and appropriate therapy instituted.

Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly.

Laboratory tests

To monitor for hematologic reactions common to all sulfonamides, it is recommended that a baseline CBC and platelet count be obtained on patients prior to initiating methazolamide therapy and at regular intervals during therapy. If significant changes occur, early discontinuance and institution of appropriate therapy are important. Periodic monitoring of serum electrolytes is also recommended.

Drug interactions

Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia.

Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose aspirin and carbonic anhydrase inhibitors (see WARNINGS).

Carcinogenesis, mutagenesis, impairment of fertility

Long-term studies in animals to evaluate the carcinogenic potential of methazolamide and its effect on fertility have not been conducted. Methazolamide was not mutagenic in the Ames bacterial test.

Pregnancy

Teratogenic effects

Pregnancy category C

Methazolamide has been shown to be teratogenic (skeletal anomalies) in rats when given in doses approximately 40 times the human dose. There are no adequate and well controlled studies in pregnant women. Methazolamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from methazolamide, 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

The safety and effectiveness of methazolamide in children have not been established.

ADVERSE REACTIONS

Adverse reactions, occurring most often early in therapy, include paresthesias, particularly a “tingling” feeling in the extremities; hearing dysfunction or tinnitus; fatigue; malaise; loss of appetite; taste alteration; gastrointestinal disturbances such as nausea, vomiting, and diarrhea; polyuria; and occasional instances of drowsiness and confusion.

Metabolic acidosis and electrolyte imbalance may occur.

Transient myopia has been reported. This condition invariably subsides upon diminution or discontinuance of the medication.

Other occasional adverse reactions include urticaria, melena, hematuria, glycosuria, hepatic insufficiency, flaccid paralysis, photosensitivity, convulsions, and, rarely, crystalluria and renal calculi. Also see PRECAUTIONS: Information for patients for possible reactions common to sulfonamide derivatives. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias (see WARNINGS).

OVERDOSAGE

No data are available regarding methazolamide overdosage in humans as no cases of acute poisoning with this drug have been reported. Animal data suggest that even a high dose of methazolamide is nontoxic. No specific antidote is known. Treatment should be symptomatic and supportive.

Electrolyte imbalance, development of an acidotic state, and central nervous system effects might be expected to occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

Supportive measures may be required to restore electrolyte and pH balance.

DOSAGE AND ADMINISTRATION

The effective therapeutic dose administered varies from 50 mg to 100 mg two or three times daily. The drug may be used concomitantly with miotic and osmotic agents.

HOW SUPPLIED

NEPTAZANETM (methazolamide tablets USP, 25 mg) are round, white tablets, debossed “EFF” on one side and “21” on the other side and are supplied in bottles of 90, NDC 48102-014-90.

NEPTAZANETM (methazolamide tablets USP, 50 mg) are round, white, scored tablets debossed “EFF” on one side and “20” on the other side and are supplied in bottles of 90, NDC 48102-015-90.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].