英文药名:Cardizem(Diltiazem Tablets)
中文药名:地尔硫卓片
药品名称
中文通用名称：盐酸地尔硫卓
英文通用名称：Diltiazem Hydrochloride
中文其它名称：盐酸硫氮卓酮, 恬尔心, 合心爽, 合贝爽, 哈氮卓, 蒂尔丁, 沁尔康, 迪尔松, 奥的镇, 奥贝-地尔硫卓, 盐酸地尔硫卓缓释胶囊, 恬尔心片, 盐酸地尔硫卓缓释片, 盐酸地尔硫卓片, 盐酸地尔硫卓注射液, 注射用盐酸地尔硫卓, 盐酸地尔硫卓控释胶囊, 盐酸地尔硫卓口服控释胶囊, 心泰, 坦立达, 盐酸地尔硫卓缓释微丸, 盐酸地尔硫卓控释片, 艾克朗, 贝洛信, 迪尔欣, 健尔信, 芊克, 太韦特, 恬尔新, 亚宝灵爽, 盐酸地尔硫卓缓释颗粒, 欣尔康, 欣太, 新益, 奥贝怡宁, 敖莱洛, 仟络爽
英文其它名称：Tildiem, Numerous, Monotildiem, Mono-Tildiem, Latlazem, Herbesser, Altiazem, Anginyl, APO-Diltiaz, Cardizem, Dilzem, Odizem, Diltiazem Hydrochloride for Injection, Diltiazem HCl CR Oral Cap SR, Diltiazem HCl Oral Cap CR, Diltiazem Hydrochloride Controlled Release Capsules, Diltiazem Hydrochloride Injection, Diltiazem Hydrochloride Sustained Release Capsules, Diltiazem Hydrochloride Sustained Release Tablets, Diltiazem Hydrochloride Tablets, Diltiazem Hydrochloride Controlled Release Tablets, Diltiazem Hydrochloride SR Capsules, Diltiazem Hydrochloride SR Microgranules, Diltiazem Hydrochloride SR Tablets, Dilzem-SR
药理作用
为钙离子拮抗剂，其电生理作用同维拉帕米。能显著的增加冠脉总血流量，降低冠状动静脉氧差，同时可增加心肌缺血区域的血流量；能降低心肌耗氧量，减轻心脏工作负荷，还具有改善心肌能量代谢，保护心肌、增加脑血流量和抗血小板聚集等作用。
规格
片剂：30mg;60mg
胶囊: 120mg;180mg;240mg;300mg
缓释片：120mg;180mg;240mg300mg;360mg;420mg
适应症
1.心绞痛，包括稳定性和不稳定性心绞痛。
2.治疗轻、中度高血压，尤其适用于伴有心绞痛的高血压。
3.高血压急症(如恶性高血压、高血压性脑病等)。
4.手术时异常高血压的急救处置。
5.用于肥厚型心肌病。
6.也用于治疗室上性快速心律失常，静脉给药可用于控制心房颤动的心室率。
用法用量
成人
*常规剂量
*口服给药
1.普通片：开始一次30mg，一日3-4次，餐前或临睡时服，每1-2日逐渐增加剂量，直到获得满意疗效。平均剂量为一日90-360mg。
2.缓释片：一次30-120mg，一日2次。用于控制稳定型心绞痛时，一次120-480mg，一日1次。
3.缓释胶囊：治疗心绞痛或高血压，先从小剂量开始，并视病情调节剂量。根据个体情况，有以下用药方案：(1)一次60mg，一日2次。(2)一次90mg，一日1-2次。(3)一次120mg，一日1次。(4)一次180-240mg，一日1次。
*静脉给药
1.控制心房颤动的心室率：初量10mg或0.15-0.25mg/kg，临用前用氯化钠注射液或葡萄糖注射液溶解、稀释为1%的溶液，在3分钟内缓慢注射。15分钟后可重复，也可按每分钟5-15μg/kg的速度静脉滴注。
2.室上性心动过速：通常为单次10mg，约3分钟内缓慢注射，可根据年龄和症状适当增减。
3.高血压急症：通常以每分钟5-15μg/kg的速度静脉滴注。
4.手术时异常高血压的急救处置：
(1)静脉注射：通常为单次10mg，约1分钟缓慢注射，可根据年龄和症状适当增减。
(2)静脉滴注：同高血压急症。
5.不稳定心绞痛：通常以每分钟1-5μg/kg的速度静脉滴注。应从小剂量开始，然后可根据病情适当增减，最大用量为每分钟5μg/kg。
*老年人剂量从小剂量开始，且给药时须仔细观察患者反应。
[国外用法用量参考]
成人
*常规剂量
*口服给药
1.慢性稳定型心绞痛或冠状动脉痉挛型心绞痛：
(1)普通片剂，起始剂量为30mg，一日3-4次。一般可用至一日180-360mg。最大日剂量为360mg。
(2)缓释胶囊，开始剂量为120mg，一日1次。通常用量为一日120-480mg，一日1次。最大日剂量为540mg，一日1次。
2.高血压：
(1)延迟释放胶囊，起始剂量为120-240mg，一日1次。通常用量为一日240-360mg，一日1次。最大日剂量为540mg，一日1次。
(2)持续释放胶囊，起始剂量为60-120mg，一日2次。通常用量为120-180mg，一日2次。最大日剂量为360mg。
3.原发性肺动脉高压：起始剂量为30mg，一日3次。通常用量为一日120-720mg，分次服用。最大日剂量为900mg，分次服用。
*静脉给药
1.心绞痛：经心室导管弹丸式注射给药，一次10mg，注射30秒。
2.室上性心律失常：用于临时控制心房颤动或心房扑动时的快心室率或阵发性室上性心动过速(PSVT)。起始剂量为0.25mg/kg(或20mg)，在2分钟内静脉注射。最大剂量为0.35mg/kg(或25mg)。如果反应不佳，可在15分钟后重复给予0.35mg/kg(或25mg)。以后再根据患者的反应确定剂量。心率减慢后即可进行持续静脉滴注，开始剂量为5mg/h，然后以5mg/h的增幅逐渐调整滴速以达满意的心室率控制。通常剂量为5-10mg/h。最大剂量为15mg/h，输注时间不超过24小时。心率得到控制后，可转为口服治疗［口服剂量=(输注速率(mg/h)×3+3)×10，在头24小时内可用本药短效制剂，以后再转为长效制剂］。
3.恶性高血压：开始剂量为5μg/(kg.min)，通常剂量可达5-40μg/(kg.min)，持续静脉输注。
*动脉给药
心肌保护：负荷量为30μg/kg，在经皮冠状动脉腔内成形术(PTCA)中应用可避免发生心肌缺血。
*肾功能不全时剂量
肾功能不全患者不需调整剂量。但应用时仍需谨慎。
*肝功能不全时剂量
本药主要在肝脏代谢，因此肝功能损害患者用量应减少。肝硬化患者一日用量低于90mg时相对较安全。
*老年人剂量
建议减少老年患者用量或延长给药间期。
*透析时剂量
血液透析、腹膜透析或持续动静脉血液滤过后无需补充剂量。
儿童
*常规剂量
*口服给药
1.高血压：
(1)儿童：普通片剂，开始剂量为一日1.5-2mg/kg，分3-4次服用。最大日剂量为3.5mg/kg。
(2)青少年：普通片剂，开始剂量为一次30mg，一日4次。通常剂量为一日180-360mg。最大日剂量为360mg；缓释胶囊，开始剂量为一次60-120mg，一日2次。通常剂量为一次120-180mg，一日2次，最大日剂量为300mg。
2.进行性假性肥大性肌营养不良：口服普通片剂，一般剂量为一日8mg/kg，分4次服用。
*静脉给药
室上性心律失常：用于暂时控制心房颤动或心房扑动时的快心室率或阵发性室上性心动过速(PSVT)。青少年开始剂量为0.25mg/kg，在2分钟内静脉注射。最大剂量为0.35mg/kg(25mg)。如果心室反应不佳，可在15分钟内重复给予0.35mg/kg(或25mg)。以后再根据病儿的反应确定剂量。心率减慢后即可进行持续静脉滴注，开始剂量为5mg/h，然后以5mg/h的增幅逐渐调整滴速以达满意的心室率控制。通常剂量为5-10mg/h。最大剂量为15mg/h，输注时间不超过24小时。
任何疑问，请遵医嘱！
给药说明
1.剂量应个体化。每日剂量分数次口服时，可在餐前或临睡时服，每1-2日逐渐增加剂量，直到获得适合的效应。停药时应逐渐减量，不能突然停药，以免出现高血压反跳或心绞痛。
2.注射剂在临用前溶解于5ml注射用水，溶解后呈无色澄明液体。如与其它制剂混合后pH超过8，可能析出结晶。
3.静脉注射本药前，明确宽QRS复合波为室上性或室性是非常重要的。
4.与其它能减慢房室结传导但不延长旁路不应期的药物(如维拉帕米和地高辛)一样，在极少数附加旁路伴房颤或房扑的患者，注射本药时可引起致命性的心率增快并伴有低血压。因此，如有可能，首次注射本药应在备有监护、复苏设备(包括直流电转复/除颤器)的病房进行。在明确患者对药物的反应后，可在常规条件接受治疗。
5.要特别注意以下3种药的联合用药(本药、β-肾上腺素受体阻断药和洋地黄制剂)。静脉给予本药和β-肾上腺素受体阻断药应避免在同时或相近的时间内给予(几小时内)。
6.皮肤反应一般是暂时的，继续用药可以消失，但也可能发展成多形性红斑和(或)剥脱性皮炎，如皮肤反应持续不退应停药。
7.药物过量：药物过量时可引起心动过缓、低血压、传导阻滞和心力衰竭。过量反应加重除应用胃肠道方法(如洗胃、活性炭吸附)去除外，基于本药药理作用和临床经验，可考虑采用以下方法：
(1)心动过缓：给予阿托品0.6-1mg，如无迷走神经阻滞效应，可谨慎应用异丙肾上腺素。如有心跳停止则须进行心脏按压、给予肾上腺素等儿茶酚胺类药物进行心脏复苏。
(2)高度房室传导阻滞：安置起搏器。
(3)心力衰竭：给予正性肌力药物(如异丙肾上腺素、多巴胺或多巴酚丁胺)和利尿药。
(4)低血压：给予升压药，如多巴胺或去甲肾上腺素。
注意事项
1.禁忌症
(1)对本药过敏者。
(2)对其它钙通道阻滞药过敏者(国外资料)。
(3)病态窦房结综合征患者。
(4)Ⅱ度以上房室传导阻滞者(安置心室起搏器者例外)。
(5)心源性休克患者(国外资料)。
(6)急性心肌梗死伴肺充血患者。
(7)存在房室旁道(如WPW综合征、LGL综合征)或短PR综合征患者合并心房颤动或心房扑动时禁止静脉给药。
(8)室性心动过速者禁止静脉给药。
(9)严重充血性心力衰竭患者。
(10)严重心肌病患者。
(11)室性心动过速患者(宽QRS波大于0.12s的心动过速患者)使用钙通道阻滞剂可能会出现血流动力学恶化和室颤)。
(12)新生儿禁用含苯甲醇的注射剂。
(13)孕妇或计划妊娠者。
2.慎用
(1)充血性心力衰竭患者。
(2)左心功能不全并使用β-肾上腺素受体阻断药的患者。
(3)低血压患者。
(4)心肌病患者。
(5)急性心肌梗死患者。
(6)Ⅰ度房室传导阻滞者。
(7)严重心动过缓(心率低于50次)者。
(8)胃肠动力增高或胃肠梗阻时慎用缓释剂(国外资料)。
(9)严重肝、肾功能不全者。
3.药物对儿童的影响 儿童用药的安全性和有效性尚未确定。新生儿禁用含苯甲醇的注射剂。
4.药物对妊娠的影响 动物实验证明，本药可致畸和致流产。对人类用药的研究尚不充分，孕妇及计划妊娠的妇女禁用注射剂。美国药品和食品管理局(FDA)对本药的妊娠安全性分级为C级。
5.药物对哺乳的影响 本药对母乳喂养的影响尚存争议，但本药可从乳汁排出，且在乳汁中的浓度接近于血药浓度，因而哺乳妇女应尽量避免使用，如必须用药时，也应暂停哺乳。
6.用药前后及用药时应当检查或监测
(1)长期给药应定期监测肝、肾功能。
(2)使用注射剂时应持续心电监护、频繁测量血压，并应配置心脏复律除颤器等急救复苏设备。
不良反应
1.发病率高于1%的有：浮肿、头痛、恶心、眩晕、皮疹、无力及心动过缓。
2.发病率低于1%有：
(1)心血管系统：低血压、心悸、晕厥、心动过速、窦房传导阻滞、严重心动过缓(有时可致心脏停搏)、房室交界性心律、期前收缩、窦性停搏、心绞痛、心律失常、房室传导阻滞(Ⅰ-Ⅲ度)、束支传导阻滞、充血性心力衰竭、心电图异常。此外有心肌梗死，但不易与本病的自然过程相鉴别。
(2)精神神经系统：多梦、遗忘、抑郁、步态异常、幻觉、失眠、神经质、感觉异常、性格改变、嗜睡、震颤、锥体外系综合征。
(3)消化系统：烦渴、味觉障碍、呕吐、畏食、便秘、腹泻、消化不良、体重增加以及碱性磷酸酶、天门冬氨酸氨基转移酶、丙氨酸氨基转移酶和乳酸脱氢酶轻度升高。
(4)皮肤：皮疹、瘙痒、光敏反应、瘀点、荨麻疹、脱发、多形性红斑以及注射部位局部发红，也有发生剥脱性皮炎的报道。
(5)血液：溶血性贫血、出血时间延长、白细胞减少、紫癜和血小板减少。
(6)泌尿生殖系统：阳萎、夜尿、多尿、少尿、血清肌酸酐和尿素氮升高。
(7)眼：弱视、视网膜病及眼激惹。
(8)其它：鼻充血、鼻出血、耳鸣、呼吸困难、高血糖、高尿酸血症、肌痉挛、骨关节痛、齿龈增生及颜面潮红。
产地：VALEANT
Pharmaceuticals North America LLC
PRINCIPAL DISPLAY PANEL - Tablet Bottle Label
Cardizem®(diltiazem HCl)
30 mg
100 Tablets
Cardizem®(diltiazem HCl)
60 mg
100 Tablets
Cardizem®(diltiazem HCl)
90 mg
100 Tablets
Cardizem®(diltiazem HCl)
120 mg
100 Tablets
CARDIZEM®(diltiazem hydrochloride)Direct Compression Tablets
Rx only
DESCRIPTION
CARDIZEM® (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, diltiazem hydrochloride is 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-. The chemical structure is:
Also contains: colloidal silicon dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake (30 mg and 90 mg), FD&C Yellow #6 Aluminum Lake (60 mg and 120 mg), hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, methylparaben, microcrystalline cellulose, and polyethylene glycol.
For oral administration.
CLINICAL PHARMACOLOGY
The therapeutic benefits achieved with CARDIZEM are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Mechanisms of Action
Although precise mechanisms of its antianginal action are still being delineated, CARDIZEM is believed to act in the following ways:
- 1.
- Angina Due to Coronary Artery Spasm. CARDIZEM has been shown to be a potent dilator of coronary arteries both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm are inhibited by CARDIZEM.
- 2.
- Exertional Angina. CARDIZEM has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal exercise workloads.
In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Hemodynamic and Electrophysiologic Effects
Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.
In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure, and in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. There are as yet few data on the interaction of diltiazem and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.
Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of CARDIZEM in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).
Chronic oral administration of CARDIZEM in doses of up to 240 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation.
Pharmacokinetics and Metabolism
Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%. CARDIZEM undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show CARDIZEM is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown CARDIZEM binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic plasma levels of CARDIZEM appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the hepatically impaired patients. A single study in nine patients with severely impaired renal functions showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal renal function.
CARDIZEM Tablets. Diltiazem is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30 to 120 mg of CARDIZEM tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of CARDIZEM tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg, daily, there is an increase in area-under-the-curve of 1.8 times.
INDICATIONS AND USAGE
CARDIZEM is indicated for the management of chronic stable angina and angina due to coronary artery spasm.
CONTRAINDICATIONS
CARDIZEM is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.
WARNINGS
1. Cardiac Conduction. CARDIZEM prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (six of 1243 patients for 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS).
2. Congestive Heart Failure. Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Experience with the use of CARDIZEM alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients.
3. Hypotension. Decreases in blood pressure associated with CARDIZEM therapy may occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to CARDIZEM is uncertain in most cases, but probable in some (see PRECAUTIONS).
PRECAUTIONS
General
CARDIZEM (diltiazem hydrochloride) is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing. Dermatological events (see ADVERSE REACTIONS) may be transient and may disappear despite continued use of CARDIZEM. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.
Drug Interactions
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving CARDIZEM concomitantly with any agents known to affect cardiac contractility and/or conduction (see WARNINGS).
Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with CARDIZEM (see WARNINGS).
As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.
Anesthetics. The depression of cardiac contractility, conductivity, and automaticity, as well as the vascular dilation associated with anesthetics, may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Benzodiazepines. Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the Cmax by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.
Beta-blockers. Controlled and uncontrolled domestic studies suggest that concomitant use of CARDIZEM and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.
Administration of CARDIZEM (diltiazem hydrochloride) concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).
Buspirone. In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.
Carbamazepine. Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40% to 72% increase) resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
Cimetidine. A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.
Clonidine. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine.
Cyclosporine. A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine trough dose ranging from 15% to 48% was necessary to maintain concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.
Digitalis. Administration of CARDIZEM with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing CARDIZEM therapy to avoid possible over- or under-digitalization (see WARNINGS).
Quinidine. Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T1/2 by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.
Rifampin. Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.
Statins. Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.
In a healthy volunteer cross-over study (N=10), co-administration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If co-administration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
In a ten-subject randomized, open label, 4-way cross-over study, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3- to 4-fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A 24-month study in rats and a 21-month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.
Pregnancy
Category C. Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.
There are no well-controlled studies in pregnant women; therefore, use CARDIZEM in pregnant women only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of CARDIZEM is deemed essential, an alternative method of infant feeding should be instituted.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities usually have been excluded.
In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during CARDIZEM therapy was not greater than that reported during placebo therapy.
The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to CARDIZEM has not been established. The most common occurrences from these studies, as well their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently (less than 1 %):
Cardiovascular: Angina, arrhythmia, AV block (first-degree), AV block (second- or third-degree – see WARNINGS, Cardiac Conduction), bradycardia, bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.
Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tremor.
Gastrointestinal: Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT, and LDH (see WARNINGS, Acute Hepatic Injury), thirst, vomiting, weight increase.
Dermatological: Petechiae, photosensitivity, pruritus, urticaria.
Other: Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, tinnitus.
The following postmarketing events have been reported infrequently in patients receiving CARDIZEM: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as myocardial infarction have been observed, which are not readily distinguishable from the natural history of the disease in these patients. A definitive cause and effect relationship between these events and CARDIZEM therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.
OVERDOSAGE
The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in overdose cases.
There have been reports of diltiazem overdose in amounts ranging from <1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.
Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.
The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.
In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered:
Bradycardia: Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.
Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.
Hypotension: Vasopressors (e.g., dopamine or norepinephrine).
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
DOSAGE AND ADMINISTRATION
Exertional Angina Pectoris Due to Atherosclerotic Coronary Artery Disease or Angina Pectoris at Rest Due to Coronary Artery Spasm
Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily, before meals and at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at 1- to 2-day intervals until optimum response is obtained. Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 360 mg/day. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.
Concomitant Use With Other Cardiovascular Agents
- 1.
- Sublingual NTG may be taken as required to abort acute anginal attacks during CARDIZEM (diltiazem hydrochloride) therapy.
- 2.
- Prophylactic Nitrate Therapy. CARDIZEM may be safely coadministered with short- and long-acting nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
- 3.
- Beta-blockers. (See WARNINGS and PRECAUTIONS).
HOW SUPPLIED
CARDIZEM 30-mg tablets are supplied in bottles of 100 (NDC 64455-771-47) and 500 (NDC 64455-771-55). Each green tablet is engraved with MARION on one side and 1771 on the other.
CARDIZEM 60-mg scored tablets are supplied in bottles of 100 (NDC 64455-772-47) and 500 (NDC 64455-772-55). Each yellow tablet is engraved with MARION on one side and 1772 on the other.
CARDIZEM 90-mg scored tablets are supplied in bottles of 100 (NDC 64455-791-47). Each green oblong tablet is engraved with CARDIZEM on one side and 90 mg on the other.
CARDIZEM 120-mg scored tablets are supplied in bottles of 100 (NDC 64455-792-47). Each yellow oblong tablet is engraved with CARDIZEM on one side and 120 mg on the other.
Store at 25°C (77°); excursions permitted to 15-30°C (59-86°) [see USP Controlled Room Temperature].