英文药名: Procardia XL(Nifedipine Extended Release Tablets)

中文药名: 硝苯地平缓释片

生产厂家: Bayer Corporation

药品名称

通用名称：硝苯地平
英文名：Nifedipine
其它中文名：利心平、尼非地平、硝苯吡啶、硝苯啶
其它英文名：Nifelat、Procardia
规格
硝苯地平胶囊5mg, 10mg；硝苯地平缓释片 20mg, 30mg, 60mg, 90mg。
药理作用
药效学
本品为一仲钙离子内流阻滞剂或慢通道阻滞剂，阻滞钙离子经过心肌或平滑肌细胞膜面的通道而进入细胞内，由此引起周身血管，包括冠状动脉(正常供血区或缺血区)的血管张力减低而扩张，因而可以降低血压，增加冠状动脉血供。并能抑制自发或麦角新碱所引起的冠状动脉痉挛。另一方面能抑制心肌收缩，使心肌作工减低，耗氧量减少，缓解心绞痛。治疗用量时对窦房结与房室结功能影响小。给本品后血压下降时可有反射性心率加速。心功能正常者给药后心脏指数略增，左心室喷血分数(LVEF)、左室舒张期末压(LVEDP) 及左室舒张期末容积(LVEDV)不变; 心功能不良者则给药后LVEF 略增而左室充盈压减低。
药动学
口服胃肠道吸收良好, 达90％左右，舌下含服吸收也快。蛋白结合率约90％, 口服30分钟血药浓度达高峰, 舌下或嚼碎服达峰时间提前。在10～30mg剂量范围内随剂量而增高, 但不受剂型与给药途径的影响。口服15分钟起效, 1～2小时作用达高峰, 作用持续4～8小时; 舌下给药2～3分钟起效, 20分钟达高峰。半衰期呈双相,半衰期α2.5～3小时, 半衰期β为5小时,半衰期受剂量影响。在肝脏代谢,产生无活性代谢产物, 80％以肾排出, 20％随粪便排出。
 
适应症　　

用于治疗高血压、心绞痛。包括冠状动脉痉挛所致的心绞痛和变异型心绞痛、冠状动脉阻塞所致的典型心绞痛或劳力性心绞痛。
本品适用于各种类型高血压病及肾性高血压的治疗，对顽固性、重度高血压及伴心力衰竭的高血压患者也有较好疗效。本品也适用于防治心绞痛，特别是变异型心绞痛和冠状动脉痉挛所致心绞痛。由于本品对呼吸功能无不良影响，故适用于患有呼吸道阻塞性疾病的心绞痛患者。对这两类疾病本品目前均为首选良药，尤其是缓释制剂产生反射性心动过速的不良反应较轻，1日服药1～2次，更为患者带来方便。此外，本品亦可用于治疗尿道梗阻或防治运动性哮喘。
用法用量　

成人常用量口服，开始一次 10mg，每日 3次，渐增至最大疗效而能耐受，剂量的增加每隔 1—2周进行 1次。住院患者可每隔 4～6小时增加 1次，每次 10mg。若按症状的发生次数和严重程度作为衡量疗效的标准，则剂量调整可以在 3天内完成，但必须严密观察监护。成人单剂最大量为 30mg，1日内总量不超过 120mg。
硝苯地平缓释片[用法用量]：
用于心绞痛，每日二次，每次一片。必要时可增加至每日二次，每次二片。
用于高血压。每日二次，每次一片。必要时可增加至每日二次，每次二片。最好在饭前或饭后服用，每次服用时间间隔不得少于 4小时。对肝、肾功能不全的病人，所开处方应谨慎，剂量应有所减少。
任何疑问，请遵医嘱！
禁用/慎用　

(1)啮齿类动物实验发现有致畸胎作用，人体研究尚不充分，在孕妇应用必须权衡利弊。
(2)在乳母的临床研究尚不够充分，服用本品者最好不授乳。
(3)在老年人本品的半衰期可能延长，应用须加注意。
(4)严重主动脉瓣狭窄、肝或肾功能不全患者须慎用。
心功能减退患者应慎用，孕妇、心源性休克者忌用。
对乙酰水杨酸和其它合成前列腺素抑制剂有过敏反应的病人，应慎用此药。
严重低血压者慎用。
给药说明　　
①长期给药不宜骤停，以避免发生停药综合征而出现反跳现象，如心绞痛发作；
②用药后注意是否有降压后出现反射性交感兴奋而心率加快以致加剧心绞痛；
③用药后，后负荷降低，也被用于治疗心力衰竭，但仅适用于高血压、冠心病所致的左心衰竭，用时还得注意有否心肌抑制的表现；
④与西咪替丁同用时本品的血药浓度峰值增高，须注意调节剂量。
服药期间必须经常测血压和做心电图检查，在开始用药而决定剂量的过程中以及从维持量加大用量时尤须注意。
少数患者初次服用本品后有首剂现象，表现为头痛、眩晕 心绞痛或心肌梗死、急性尿潴留等，故对心功能减退患者应慎用，一旦发生心肌缺血症状应立即停药。
日剂量大于120mg时，突然停药会产生撤药综合征，主要表现为心绞痛的复发或频繁发作。其原因与心肌细胞长期缺钙后对钙处于高敏状态，一旦停药，正常量钙离子进入细胞内即可产生过量的反应。
长期服药宜与利尿剂合用。
不良反应　
(1)反应短暂而较多见的是踝、足与小腿肿胀，用利尿药可消退；较少见的是呼吸困难、咳嗽、哮鸣、心跳快而重(由于降压后交感活性反射性增强；罕见的是胸痛(可出现于用药后 30分钟左右)、昏厥(血压过低所致)、胆石症、过敏性肝炎。
(2)反应持续出现而须加注意的有；眩晕、头昏、脸红及热感、头痛、恶心。
(3)逾量时可出现低血压，此时应停药观察，必要时用血管收缩药。
白细胞减少, 颜面或皮肤潮红, 心悸, 心动过速。个别病例舌根或口周麻木, 口干, 出汗, 头痛, 恶心, 浮肿, 男性乳房增大,视物模糊。个别病例出现心肌梗塞, 皮肤坏死, 局部组织损伤。可引起肝损害。
一般较轻，主要有头痛、乏力、颜面潮红、心悸、嗜睡、眩晕、恶心、呕吐、口干、便秘、食欲减退、腿部痉挛、舌根麻木、牙龈肿胀等。长期服用可能引起水钠潴留，水肿，多发生于踝部，偶见于脸部及眶周；剂量过大时可引起心动过缓及低血压。
也有报告发生暂时性视网膜缺血者。有报告发生易激动、震颤、好斗、抑郁、小腿及手部肌肉严重挛缩、恶梦及幻视。
此药可致肝脏损害。有报告此药可致肾功能不全、粒细胞减少者。
有报告发生末梢水肿，特别是小腿。有发生红斑伴疼痛及水肿、对光敏感及周身大疱疹。
有报告此药使患者在运动时出现双眼视物不清。有发生牙龈增生者，它与环孢素(Ciclosporin)合用则牙龈增生的发生率更高。有发生味觉及嗅觉异常者，停药24小时内即恢复正常。
药物相互作用
(1)与其他降压药同用可致极度低血压。
(2)与 β阻滞剂同用可导致血压过低、心功能抑制，心力衰竭发生的机会增多。
(3)突然停用 β阻滞剂治疗而启用本品，偶可发生心绞痛，须逐步递减前者用量。
(4)与蛋白结合率高的药物如双香豆素、洋地黄苷类、苯妥英钠、奎尼丁、奎宁、华法林等同用，这些药的游离浓度常发生改变。
(5)与硝酸酯类同用，可使心绞痛作用增强。本品与多数降压药物合用具协同降压作用，但一般不与哌唑嗪合用以免引起血压过度下降，也不与β受体阻滞药合用以防过度抑制心肌，出现心力衰竭或加重心绞痛及产生严重低血压。地尔硫卓可抑制本品氧化代谢，使硝苯地平血药浓度增加。本品可能增加地高辛血药浓度，故与地高辛合用时，应注意调整地高辛剂量。
它也使苯妥英浓度升高。它使奎尼丁排除增多，使奎尼丁的抗心律失常作用减低。它与哌唑嗪合用可导致急性低血压症。
有些药物(抗凝血剂、血小板凝聚抑制剂、胰岛素和口服抗糖尿病药)不应与本药合用。
本品可与其它抗高血压药物合用，有协同作用，应注意有时造成血压过低。
与心得安、洋地黄甙类、甲腈咪胍、利福平、苯妥英钠及葡萄柚汁等同服，可改变血药浓度及降压效果，应注意。

Procardia XL®
(nifedipine)
Extended Release Tablets
For Oral Use
Procardia XL Description
Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C17H18N2O6, and has the structural formula:

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Procardia XL is a registered trademark for Nifedipine GITS. Nifedipine GITS (Gastrointestinal Therapeutic System) Tablet is formulated as a once-a-day controlled-release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine.

Inert ingredients in the formulations are: cellulose acetate; hydroxypropyl cellulose; hypromellose; magnesium stearate; polyethylene glycol; polyethylene oxide; red ferric oxide; sodium chloride; titanium dioxide.

System Components and Performance

Procardia XL® Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer.

Procardia XL Extended Release Tablet is designed to provide nifedipine at an approximately constant rate over 24 hours. This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. Procardia XL depends for its action on the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the gastrointestinal tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

Procardia XL - Clinical Pharmacology

Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without altering serum calcium concentrations.

Mechanism of Action

A) Angina

The precise mechanisms by which inhibition of calcium influx relieves angina has not been fully determined, but includes at least the following two mechanisms:

1) Relaxation and Prevention of Coronary Artery Spasm

Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of nifedipine in vasospastic (Prinzmetal's or variant) angina. Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.

2) Reduction of Oxygen Utilization

Nifedipine regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral vascular resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements, and probably accounts for the effectiveness of nifedipine in chronic stable angina.

B) Hypertension

The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.

Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.

Pharmacokinetics and Metabolism

Nifedipine is completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate after a Procardia XL Extended Release Tablet dose and reach a plateau at approximately six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24-hour dosing interval. About a four-fold higher fluctuation index (ratio of peak to trough plasma concentration) was observed with the conventional immediate-release PROCARDIA® capsule at t.i.d. dosing than with once daily Procardia XL Extended Release Tablet. At steady-state, the bioavailability of the Procardia XL Extended Release Tablet is 86% relative to PROCARDIA capsules. Administration of the Procardia XL Extended Release Tablet in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced gastrointestinal retention time over prolonged periods (i.e., short bowel syndrome), however, may influence the pharmacokinetic profile of the drug which could potentially result in lower plasma concentrations. Pharmacokinetics of Procardia XL Extended Release Tablets are linear over the dose range of 30 to 180 mg in that plasma drug concentrations are proportional to dose administered. There was no evidence of dose dumping either in the presence or absence of food for over 150 subjects in pharmacokinetic studies.

Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites, accounting for 60 to 80% of the dose excreted in the urine. The elimination half-life of nifedipine is approximately two hours. Only traces (less than 0.1% of the dose) of unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion. Thus, the pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment. Patients in hemodialysis or chronic ambulatory peritoneal dialysis have not reported significantly altered pharmacokinetics of nifedipine. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92–98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.

Hemodynamics

Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5–10 mm Hg systolic), but sometimes larger. With Procardia XL Extended Release Tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP), or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.

Electrophysiologic Effects

Although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate.

Indications and Usage for Procardia XL

I. Vasospastic Angina

Procardia XL is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Procardia XL may also be used where the clinical presentation suggests a possible vasospastic component, but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion, or in unstable angina where electrocardiographic findings are compatible with intermittent vasospasm, or when angina is refractory to nitrates and/or adequate doses of beta blockers.

II. Chronic Stable Angina
     (Classical Effort-Associated Angina)

Procardia XL is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta blockers and/or organic nitrates or who cannot tolerate those agents.

In chronic stable angina (effort-associated angina), nifedipine has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients is incomplete.

Controlled studies in small numbers of patients suggest concomitant use of nifedipine and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely, since severe hypotension can occur from the combined effects of the drugs. (See WARNINGS.)

III. Hypertension

Procardia XL is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

Contraindications

Known hypersensitivity reaction to nifedipine.

Warnings

Excessive Hypotension

Although in most angina patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta blockers.

Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of nifedipine and a beta blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient's condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery.

The following information should be taken into account in those patients who are being treated for hypertension as well as angina:

Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established.

Beta Blocker Withdrawal

It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine. Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it.

Congestive Heart Failure

Rarely, patients, usually receiving a beta blocker, have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit, owing to the fixed impedance to flow across the aortic valve in these patients.

Gastrointestinal Obstruction Requiring Surgery

There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of Procardia XL. Bezoars can occur in very rare cases and may require surgical intervention.

Cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention.

Risk factors for a gastrointestinal obstruction identified from post-marketing reports of Procardia XL (GITS tablet formulation) include alteration in gastrointestinal anatomy (e.g., severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (e.g., constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (e.g., H2-histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).

Gastrointestinal Ulcers

Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

Precautions

General—Hypotension

Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure. (See WARNINGS.)

Peripheral Edema

Mild to moderate peripheral edema occurs in a dose dependent manner with an incidence ranging from approximately 10% to about 30% at the highest dose studied (180 mg). It is a localized phenomenon thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose angina or hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

Information for Patients

Procardia XL Extended Release Tablets should be swallowed whole. Do not chew, divide or crush tablets. Do not be concerned if you occasionally notice in your stool something that looks like a tablet. In Procardia XL, the medication is contained within a nonabsorbable shell that has been specially designed to slowly release the drug for your body to absorb. When this process is completed, the empty tablet is eliminated from your body.

Laboratory Tests

Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundice has been reported. A small (5.4%) increase in mean alkaline phosphatase was noted in patients treated with Procardia XL. This was an isolated finding not associated with clinical symptoms and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported. In controlled studies, Procardia XL did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving Procardia XL in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.

Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and an increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.

Positive direct Coombs test with/without hemolytic anemia has been reported, but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.

Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and serum creatinine have been reported in patients with preexisting chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.

Drug Interactions

Beta-adrenergic blocking agents

(See INDICATIONS AND USAGE and WARNINGS.) Experience in over 1400 patients with PROCARDIA capsules in a noncomparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina.

Long-acting Nitrates

Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Digitalis

Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization.

Coumarin Anticoagulants

There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain.

Cimetidine

A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.

Pregnancy

Pregnancy Category C

Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (3.5 to 42 times) than the maximum recommended human dose of 120 mg/day. On a mg/m2 basis, some doses were higher and some were lower than the maximum recommended human dose, but all are within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m2 basis.

There are no adequate and well-controlled studies in pregnant women. Procardia XL Extended Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE EXPERIENCES

Over 1000 patients from both controlled and open trials with Procardia XL Extended Release Tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during Procardia XL Extended Release Tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with Procardia XL was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experiences reported in placebo-controlled trials include:

Adverse Effect	Procardia XL (%) (N=707)	Placebo (%) (N=266)
Headache	15.8	9.8
Fatigue	5.9	4.1
Dizziness	4.1	4.5
Constipation	3.3	2.3
Nausea	3.3	1.9

Of these, only edema and headache were more common in Procardia XL patients than placebo patients.

The following adverse reactions occurred with an incidence of less than 3.0%. With the exception of leg cramps, the incidence of these side effects was similar to that of placebo alone.

Body as a Whole/Systemic: asthenia, flushing, pain
Cardiovascular: palpitations
Central Nervous System: insomnia, nervousness, paresthesia, somnolence
Dermatologic: pruritus, rash
Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence
Musculoskeletal: arthralgia, leg cramps
Respiratory: chest pain (nonspecific), dyspnea
Urogenital: impotence, polyuria

Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include:

Body as a Whole/Systemic: face edema, fever, hot flashes, malaise, periorbital edema, rigors
Cardiovascular: arrhythmia, hypotension, increased angina, tachycardia, syncope
Central Nervous System: anxiety, ataxia, decreased libido, depression, hypertonia, hypoesthesia, migraine, paroniria, tremor, vertigo
Dermatologic: alopecia, increased sweating, urticaria, purpura
Gastrointestinal: eructation, gastroesophageal reflux, gum hyperplasia, melena, vomiting, weight increase
Musculoskeletal: back pain, gout, myalgias
Respiratory: coughing, epistaxis, upper respiratory tract infection, respiratory disorder, sinusitis
Special Senses: abnormal lacrimation, abnormal vision, taste perversion, tinnitus
Urogenital/Reproductive: breast pain, dysuria, hematuria, nocturia

Adverse experiences which occurred in less than 1 in 1000 patients cannot be distinguished from concurrent disease states or medications.

The following adverse experiences, reported in less than 1% of patients, occurred under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain: gastrointestinal irritation, gastrointestinal bleeding, gynecomastia.

Gastrointestinal obstruction resulting in hospitalization and surgery, including the need for bezoar removal, has occurred in association with Procardia XL, even in patients with no prior history of gastrointestinal disease. (See WARNINGS.)

Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

In multiple-dose U.S. and foreign controlled studies with nifedipine capsules in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of nifedipine.

Adverse Effect	PROCARDIA CAPSULES (%) (N=226)	Placebo (%) (N=235)
Dizziness, lightheadedness, giddiness	27	15
Flushing, heat sensation	25	8
Headache	23	20
Weakness	12	10
Nausea, heartburn	11	8
Muscle cramps, tremor	8	3
Peripheral edema	7	1
Nervousness, mood changes	7	4
Palpitations	7	5
Dyspnea, cough, wheezing	6	3
Nasal congestion, sore throat	6	8

There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The relatively common adverse events were similar in nature to those seen with Procardia XL.

In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.

In a subgroup of over 1000 patients receiving PROCARDIA with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of PROCARDIA-treated patients. (See PRECAUTIONS.)

In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.

In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported.

Overdosage

Experience with nifedipine overdosage is limited. Generally, overdosage with nifedipine leading to pronounced hypotension calls for active cardiovascular support, including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents, and fluids. Clearance of nifedipine would be expected to be prolonged in patients with impaired liver function. Since nifedipine is highly protein-bound, dialysis is not likely to be of any benefit.

There has been one reported case of massive overdosage with Procardia XL Extended Release Tablets. The main effects of ingestion of approximately 4800 mg of Procardia XL in a young man attempting suicide as a result of cocaine-induced depression was initial dizziness, palpitations, flushing, and nervousness. Within several hours of ingestion, nausea, vomiting, and generalized edema developed. No significant hypotension was apparent at presentation, 18 hours post-ingestion. Electrolyte abnormalities consisted of a mild, transient elevation of serum creatinine, and modest elevations of LDH and CPK, but normal SGOT. Vital signs remained stable, no electrocardiographic abnormalities were noted, and renal function returned to normal within 24 to 48 hours with routine supportive measures alone. No prolonged sequelae were observed.

The effect of a single 900 mg ingestion of PROCARDIA capsules in a depressed anginal patient also on tricyclic antidepressants was loss of consciousness within 30 minutes of ingestion, and profound hypotension, which responded to calcium infusion, pressor agents, and fluid replacement. A variety of ECG abnormalities were seen in this patient with a history of bundle branch block, including sinus bradycardia and varying degrees of AV block. These dictated the prophylactic placement of a temporary ventricular pacemaker, but otherwise resolved spontaneously. Significant hyperglycemia was seen initially in this patient, but plasma glucose levels rapidly normalized without further treatment.

A young hypertensive patient with advanced renal failure ingested 280 mg of PROCARDIA capsules at one time, with resulting marked hypotension responding to calcium infusion and fluids. No AV conduction abnormalities, arrhythmias, or pronounced changes in heart rate were noted, nor was there any further deterioration in renal function.

Procardia XL Dosage and Administration

Dosage must be adjusted according to each patient's needs. Therapy for either hypertension or angina should be initiated with 30 or 60 mg once daily. Procardia XL Extended Release Tablets should be swallowed whole and should not be bitten or divided. In general, titration should proceed over a 7–14 day period so that the physician can fully assess the response to each dose level and monitor blood pressure before proceeding to higher doses. Since steady-state plasma levels are achieved on the second day of dosing, titration may proceed more rapidly, if symptoms so warrant, provided the patient is assessed frequently. Titration to doses above 120 mg are not recommended.

Angina patients controlled on PROCARDIA capsules alone or in combination with other antianginal medications may be safely switched to Procardia XL Extended Release Tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d. of PROCARDIA capsules may be changed to 90 mg once daily of Procardia XL Extended Release Tablets). Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. Experience with doses greater than 90 mg in patients with angina is limited. Therefore, doses greater than 90 mg should be used with caution and only when clinically warranted.

No "rebound effect" has been observed upon discontinuation of Procardia XL Extended Release Tablets. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision.

Care should be taken when dispensing Procardia XL to assure that the extended release dosage form has been prescribed.

Co-Administration with Other Antianginal Drugs

Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See PRECAUTIONS, Drug Interactions, for information on co-administration of nifedipine with beta blockers or long-acting nitrates.

How is Procardia XL Supplied

Procardia XL Extended Release Tablets are supplied as 30 mg, 60 mg and 90 mg round, biconvex, rose-pink, film-coated tablets in:

Store below 86°F (30°C).

包装规格：
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注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
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·Procardia XL 20mg *84 片
·Procardia XL 30mg *84 片
·Procardia XL 60mg *84 片
·Procardia XL 10mg *100片
·Procardia XL 20mg *100片
·Procardia XL 30mg *100片 
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以下生产厂家：辉瑞（PFIZER ）
·PROCARDIA XL OSM缓释片 30毫克/片 300片/盒
·PROCARDIA XL OSM缓释片 30毫克/片 100片/盒
·PROCARDIA XL OSM缓释片 60毫克/片 100片/盒
·PROCARDIA XL OSM缓释片 90毫克/片 100片/盒