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【药物名称】Verapamil, Calan, Securon, Cordilox, Verelan PM, Chronovera,
Covera-HS(controlled onset, extended release system), Isoptin(HCl)
【化学名】5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
【类别】钙通道阻滞药。
【药理毒理】
本品为钙离子拮抗剂，能选择性扩张冠状动脉，增加冠脉流量；能抑制心肌兴奋性及房室传导。用于治疗阵发性室上性心动过速。
【药动学】
口服吸收完全约30min起效，维持5～8h。Tmax约30～45min，肝首过效应明显，PB90%，T1/2约3～12h，。静注后1～2min开始作用，作用持续15min。T1/2β约2～5h，长期用药或肝肾功能不全时延长。血液透析不能清除本品。
【适应症】
1.心绞痛：变异型心绞痛；不稳定性心绞痛；慢性稳定性心绞痛。
2.心律失常：与地高辛合用控制慢性心房颤动和/或心房扑动时的心室率；预防阵发性室上性心动过速的反复发作。
3.原发性高血压。
【用法用量】
通过调整剂量达到个体化治疗。安全有效的剂量为不超过480mg/日。
1.心绞痛：一般剂量为口服维拉帕米80～120mg/次，一日三次。肝功能不全者及老年人的安全剂量为40mg/次，一日三次口服。约在药后8小时根据疗效和安全评估决定是否增量。
2.心律失常：慢性心房颤动服用洋地黄治疗的病人，每日总量为240～320mg，分三次或四次/日口服。预防阵发性室上性心动过速（未服用洋地黄的病人）成人的每日总量为240～480mg，一日三次或四次口服。年龄1～5岁：每日量4～8mg/Kg，一日分三次口服；或每隔8小时口服。
任何疑问，请遵医嘱！
【不良反应】
以推荐的单剂量和每日总量为起始剂量并逐渐向上调整剂量用药，严重不良反应少见。
发生率在1～10%的不良反应：便秘（7.3%）；眩晕、轻度头痛（3.5%）；恶心（2.7%）；低血压（2.5%）；头痛（2.2%）。外周水肿（2.1%）；充血性心力衰竭（1.8%）；窦性心动过缓，I度、II度或III度房室阻滞；皮疹（1.2%）；乏力；心悸；转氨酶升高，伴或不伴碱性磷酸酶和胆红素的升高，这种升高有时是一过性的，甚至继续使用维拉帕米仍可消失。
发生率<1%的不良反应：低血压；心动过速；潮红；溢乳；牙龈增生；非梗阻性麻痹性肠梗阻等。
【注意事项】
1 心力衰竭：维拉帕米的负性肌力作用可因其减轻后负荷（降低循环血管阻力）而代偿，净效应不损害心室功能。但是严重左心室功能不全（肺楔压大于20mmHg或射血分数小于30%）、中-重度心力衰竭的病人、已接受β受体阻滞剂治疗的任何程度的心室功能障碍的病人，避免使用维拉帕米。必须使用维拉帕米的轻度心功能不全的病人，治疗之前需已有洋地黄类或利尿剂控制临床症状。
2 预激综合症：维拉帕米会加速房室旁路前向传导。房室旁路通道合并心房扑动或心房颤动病人静脉用维拉帕米治疗，会通过加速房室旁路的前向传导，引起心室率加快，甚至诱发心室颤动。虽然口服维拉帕米未见上述报道，但这种病人接受口服维拉帕米可能有危险，因此禁止使用。
3 传导阻滞：维拉帕米可能导致房室结和窦房结传导阻滞，与血浆浓度增高相关，尤其是在治疗早期的增量期。引起I度房室阻滞、一过性窦性心动过缓，有时伴有结性逸搏。高度房室传导阻滞不常见（0.8%）。当出现显著的I度房室传导阻滞或逐渐发展成II或III度房室传导阻滞时，需要减量或停药。
4 肝功能损害：因维拉帕米在肝内广泛代谢，肝功能损害的病人慎用维拉帕米。严重肝功能不全时维拉帕米的清除半衰期延长至14～16小时，该类病人只需服用正常剂量的30%。
5 肾功能损害：肾功能损害的病人慎用维拉帕米。血液透析不能清除维拉帕米。
6 神经肌肉传导减弱：有报道维拉帕米减弱肌肉萎缩病人的神经肌肉传导，该类病人可能需要减量。
7 血清钙：维拉帕米不改变血清钙浓度，但也有高于正常范围的血钙水平可能影响维拉帕米疗效的报道。
8 因维拉帕米可引起转氨酶增高，为慎重起见，接受维拉帕米治疗的患者应定期监测肝功能。
【禁忌】
1 严重左心室功能不全。
2 低血压（收缩压小于90mmHg）或心源性休克。
3 病窦综合征（已安装并行使功能的心脏起搏器病人除外）。
4 II或III度房室阻滞（已安装并行使功能的心脏起搏器病人除外）。
5 心房扑动或心房颤动病人合并房室旁路通道。
6 已知对盐酸维拉帕米过敏的病人。
【药物相互作用】
1 环磷酰胺、长春新碱、甲基苄肼、强的松、长春碱酰胺、阿霉素、顺铂等细胞毒性药物减少维拉帕米的吸收。
2 苯巴比妥、乙内酰脲、维生素D、苯磺唑酮和雷米封通过增加肝脏代谢降低维拉帕米的血浆浓度。
3 西米替丁可能提高维拉帕米的生物利用度。
4 维拉帕米抑制乙醇的消除，导致血中乙醇浓度增加，可能延长酒精的毒性作用。
5 少数病例报道维拉帕米和阿斯匹林合用，出血时间较单独使用阿斯匹林时延长。
6 与β受体阻滞剂联合使用, 可增强对房室传导的抑制作用。
7 长期服用维拉帕米，使地高辛血药浓度增加50～75%。维拉帕米明显影响肝硬化病人地高辛的药代动力学，使地高辛的总清除率和肾外清除率分别减少27%和29%。因此服用维拉帕米时，须减少地高辛和洋地黄的剂量。
8 与血管扩张剂、血管紧张素转换酶抑制剂、利尿剂等抗高血压药合用时，降压作用叠加，应适当监测联合降压治疗的病人。
9 与胺碘酮合用可能增加心脏毒性。
10 肥厚性心肌病主动脉瓣下狭窄的病人, 最好避免联合用药。
11 维拉帕米与氟卡胺合用，可使负性肌力作用叠加，房室传导延长。
12 维拉帕米可增加卡马西平、环胞素、阿霉素、茶碱的血药浓度。
13 有报道维拉帕米增加病人对锂的敏感性（神经毒性）。
14 动物实验提示吸入性麻醉剂与维拉帕米同时使用时，需仔细调整两药剂量，避免过度抑制心脏。
15 避免维拉帕米与丙吡胺同时使用。
【药物过量】
维拉帕米过量后出现的症状与服用的剂量、开始解毒的时间以及患者的心肌收缩能力(年龄相关)有关。在严重的维拉帕米中毒的病例中可出现下列情况：意识障碍(意识模糊到昏迷)、血压下降、心动过缓、心动过速、高血糖症、钾缺失、代谢性酸中毒、低氧血症、心源性休克伴肺水肿。
DESCRIPTION
Verelan® (verapamil hydrochloride capsules) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verelan is available for oral administration as a 360 mg hard gelatin capsule (lavender cap/yellow body), a 240 mg hard gelatin capsule (dark blue cap/yellow body), a 180 mg hard gelatin capsule (light grey cap/yellow body), and a 120 mg hard gelatin capsule (yellow cap/yellow body). These pellet filled capsules provide a sustained-release of the drug in the gastrointestinal tract.
The structural formula of verapamil HCl is given below:
Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl), monohydrochloride.
Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not structurally related to other cardioactive drugs.
In addition to verapamil HCl the Verelan capsule contains the following inactive ingredients: fumaric acid, talc, sugar spheres, povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and sodium lauryl sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the Verelan 180 mg capsule contains black iron oxide.
image of chemical structure CLINICAL PHARMACOLOGY
Verelan is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells.
Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects. (See WARNINGS. ) Verapamil HCl does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil HCl may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. (See WARNINGS. )
Verapamil HCl has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.
Mechanism of Action Essential Hypertension
Verapamil HCl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil HCl regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works.
Pharmacokinetics and Metabolism
With the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil HCl dose administered and verapamil plasma levels does exist.
During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized.
In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of Verelan 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, Verelan was shown to have a similar extent of verapamil bioavailability based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study Verelan doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for the Verelan 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng∙hr/mL):3 (1660 ng∙hr/mL):5 (2729 ng∙hr/mL) and 1 (621 ng∙hr/mL):3 (1614 ng∙ hr/mL):4 (2535 ng∙hr/mL) respectively, indicating that the AUC increased non-proportionately with increasing doses.
Food does not affect the extent or rate of the absorption of verapamil from the controlled release Verelan capsule. The Verelan 240 mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(O-inf) of 1387 ng∙hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(O-inf) of 1541 ng∙hr/mL.
The bioequivalence of Verelan 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for Cmax, Tmax, and AUC(O-inf) respectively. When the contents of the Verelan® capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Similar results were observed with norverapamil.
The time to reach maximum verapamil concentrations (Tmax) with Verelan has been found to be approximately 7-9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic studies. Similarly the apparent half-life (t1/2) has been found to be approximately 12 hours independent of dose. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.
In healthy man, orally administered verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately 20% that of verapamil.
Approximately 70% of an administered dose of verapamil HCl is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS ), the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of the oral daily dose required for patients with normal liver function.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo. (See PRECAUTIONS-Drug Interactions. )
The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg∙hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values.
Geriatric Use
The pharmacokinetics of verapamil GITS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years) versus 30 healthy elderly (65-80years) male and female subjects. Older subjects had significantly higher mean verapamil Cmax , Cmin and AUC (0-24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7-2.0 times higher than those of younger subjects as well as a longer average verapamil t1/2 (approximately 20 hr vs. 13 hr).
Hemodynamics and Myocardial Metabolism
Verapamil HCl reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with verapamil HCl therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil HCl is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur. (See Drug Interactions. )
Pulmonary Function
Verapamil HCl does not induce broncho-constriction and hence, does not impair ventilatory function.
INDICATIONS AND USAGE
Verelan (verapamil HCl) is indicated for the management of essential hypertension.
CONTRAINDICATIONS
Verapamil HCl is contraindicated in:
1.Severe left ventricular dysfunction. (See WARNINGS. )
2.Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.
3.Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
4.Second - or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
5.Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See WARNINGS. )
6.Patients with known hypersensitivity to Verapamil hydrochloride.
WARNINGS
Heart Failure
Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See Drug Interactions. ) Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note interactions with digoxin under: PRECAUTIONS ).
Hypotension
Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.
Elevated Liver Enzymes
Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong- Levine)
Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. (See CONTRAINDICATIONS. )
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Atrioventricular Block
The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed.
Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.
Patients with Hypertrophic Cardiomyopathy (IHSS)
In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug Interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.
PRECAUTIONS
THE CONTENTS OF THE Verelan CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE (See DOSAGE AND ADMINISTRATION ).
General Use in Patients with Impaired Hepatic Function
Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE ) should be carried out.
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.
Use in Patients with Impaired Renal Function
About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE. )
Information for Patients
When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See DOSAGE AND ADMINISTRATION .)
Drug-Drug Interactions Drug Interactions: Effects of other drugs on verapamil pharmacokinetics
In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (eg, erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (eg, rifampin) have caused a lowering of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin , an antibiotic in the ketolide class of antibiotics.
Beta Blockers
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension.
For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has not been observed when verapamil and atenolol are given together.
Clonidine
Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.
Digitalis
Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy.
In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.
Antihypertensive Agents
Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.
Antiarrhythmic Agents Disopyramide
Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.
Flecainide
A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.
Quinidine
In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.
Nitrates
Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Alcohol
Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY-Pharmacokinetics and Metabolism.)
Other Aspirin
In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.
Cimetidine
The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.
Grapefruit juice
Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.
Lithium
Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.
Carbamazepine
Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Rifampin
Therapy with rifampin may markedly reduce oral verapamil bioavailability.
Phenobarbital
Phenobarbital therapy may increase verapamil clearance.
Cyclosporine
Verapamil therapy may increase serum levels of cyclosporine.
Inhalation Anesthetics
Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents
Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
Carcinogenesis, Mutagenesis, Impairment of Fertility
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
Pregnancy Pregnancy Category C
Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.
Labor and Delivery
It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil HCl in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.
Nursing Mothers
Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.
Pediatric Use
Safety and efficacy of verapamil in children below the age of 18 years have not been established.
Geriatric Use
Clinical studies of verapamil 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.
Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ).
Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS, General ). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND ADMINISTRATION ).
Animal Pharmacology and/or Animal Toxicology
In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.
ADVERSE REACTIONS
Serious adverse reactions are uncommon when verapamil HCl therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.
In clinical trials involving 285 hypertensive patients on Verelan for greater than 1 week the following adverse reactions were reported in greater than 1.0% of the patients:
| Constipation |
7.4% |
| Headache |
5.3% |
| Dizziness |
4.2% |
| Lethargy |
3.2% |
| Dyspepsia |
2.5% |
| Rash |
1.4% |
| Ankle Edema |
1.4% |
| Sleep Disturbance |
1.4% |
| Myalgia |
1.1% | In clinical trials of other formulations of verapamil HCl (N=4,954) the following reactions have occurred at rates greater than 1.0%:
| Constipation |
7.3% |
| CHF/Pulmonary Edema |
1.8% |
| Dizziness |
3.3% |
| Fatigue |
1.7% |
| Nausea |
2.7% |
| Bradycardia (HR less than 50/min) |
1.4% |
| Hypotension |
2.5% |
| AV block-total 1°, 2°, 3° |
1.2% |
| 2° and 3° |
0.8% |
| Edema |
1.9% |
| Headache |
2.2% |
| Flushing |
0.6% |
| Rash |
1.2% |
| Elevated Liver Enzymes (see WARNINGS ) | In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.
The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.
Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.
Hemic and Lymphatic: ecchymosis or bruising.
Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.
Respiratory: dyspnea.
Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.
Special Senses: blurred vision, tinnitus.
Urogenital: gynecomastia, impotence, increased urination, spotty menstruation.
Treatment of Acute Cardiovascular Adverse Reactions
The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician.
OVERDOSAGE
There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may occur with sustained-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of non-cardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9g).
In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium, inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1g/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis.
DOSAGE AND ADMINISTRATION
Essential Hypertension
The dose of Verelan should be individualized by titration. The usual daily dose of sustained-release verapamil, Verelan, in clinical trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan are evident within the first week of therapy.
If adequate response is not obtained with 120 mg of Verelan, the dose may be titrated upward in the following manner:
(a) 180 mg in the morning.
(b) 240 mg in the morning.
(c) 360 mg in the morning.
(d) 480 mg in the morning.
Verelan sustained-release capsules are for once-a-day administration. When switching from immediate-release verapamil to Verelan capsules, the same total daily dose of Verelan capsules can be used.
As with immediate-release verapamil, dosages of Verelan capsules should be individualized and titration may be needed in some patients.
Sprinkling the Capsule Contents on Food
Verelan pellet filled capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any pellet/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a Verelan capsule is not recommended.
Store at controlled room temperature 20°-25°C (68°-77°F). [See USP]. Avoid excessive heat. Brief digressions above 25°C, while not detrimental, should be avoided. Protect from moisture. Dispense in tight, light-resistant container as defined in USP.
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注：以下产品规格和价格均不同，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:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 240MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 240毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 180MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 180毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
--------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 120MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 120毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 360MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 360毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
---------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 300MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 300毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 200MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 200毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
----------------------------------------------------------
产地国家: 美国
原产地英文商品名:
VERAPAMIL SR CAPSULE 24H(VERELAN GENERIC) 100MG/CAP 100CAPS/BOTTLE
原产地英文药品名:
VERAPAMIL HCL
原产地英文化合物名称:
5-[N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
中文参考商品译名:
维拉帕米24小时缓释胶囊(VERELAN仿制药) 100毫克/胶囊 100胶囊/瓶
中文参考药品译名:
盐酸维拉帕米
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