英文药名: Procardia(Nifedipine Capsules) 中文药名: 硝苯地平胶囊,硝苯吡啶,心痛定,拜心通,艾克地平,爱地平 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(nifedipine) capsule [Pfizer Laboratories Div Pfizer Inc] DESCRIPTION PROCARDIA® (nifedipine) is an antianginal drug belonging to a class of pharmacological agents, 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 capsules are formulated as soft gelatin capsules for oral administration, each containing 10 mg nifedipine. Inert ingredients in the formulation are: glycerin; peppermint oil; polyethylene glycol; soft gelatin capsules (which contain Yellow 6, and may contain Red Ferric Oxide and other inert ingredients); and water. The 10 mg capsules also contain saccharin sodium. CLINICAL PHARMACOLOGY PROCARDIA 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. PROCARDIA selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without changing serum calcium concentrations. Mechanism of Action The precise means by which this inhibition relieves angina has not been fully determined, but includes at least the following two mechanisms: 1) Relaxation and Prevention of Coronary Artery Spasm PROCARDIA 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 PROCARDIA 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 PROCARDIA 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. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of PROCARDIA in chronic stable angina. Pharmacokinetics and Metabolism PROCARDIA is rapidly and fully absorbed after oral administration. The drug is detectable in serum 10 minutes after oral administration, and peak blood levels occur in approximately 30 minutes. Bioavailability is proportional to dose from 10 to 30 mg; half-life does not change significantly with dose. There is little difference in relative bioavailability when PROCARDIA capsules are given orally and either swallowed whole, bitten and swallowed, or bitten and held sublingually. However, biting through the capsule prior to swallowing does result in slightly earlier plasma concentrations (27 ng/mL 10 minutes after 10 mg) than if capsules are swallowed intact. PROCARDIA is highly bound by serum proteins. PROCARDIA is extensively converted to inactive metabolites and approximately 80 percent of PROCARDIA and metabolites are eliminated via the kidneys. The half-life of nifedipine in plasma is approximately two hours. 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. In healthy subjects, the elimination half-life of a BID sustained release nifedipine formulation [that was neither Procardia capsules nor Procardia XL (nifedipine) extended release tablets] was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) following intravenous administration. Co-administration of nifedipine with grapefruit juice resulted in approximately a 2-fold increase in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are most likely due to inhibition of CYP 3A4 related first-pass metabolism. Hemodynamics Like other slow-channel blockers, PROCARDIA 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, PROCARDIA causes decreased peripheral vascular resistance and a fall in systolic and diastolic pressure, usually modest (5–10 mm Hg systolic), but sometimes larger. There is usually a small increase in heart rate, a reflex response to vasodilation. Measurements of cardiac function 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, PROCARDIA decreases 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, PROCARDIA has had no tendency to prolong atrioventricular conduction, prolong sinus node recovery time, or slow sinus rate. INDICATIONS AND USAGE I. Vasospastic Angina PROCARDIA (nifedipine) 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 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 when angina is refractory to nitrates and/or adequate doses of beta blockers. II. Chronic Stable Angina     (Classical Effort-Associated Angina) PROCARDIA 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), PROCARDIA 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 are incomplete. Controlled studies in small numbers of patients suggest concomitant use of PROCARDIA 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.) CONTRAINDICATIONS Known hypersensitivity reaction to PROCARDIA. WARNINGS Excessive Hypotension Although, in most patients, the hypotensive effect of PROCARDIA 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. Although patients have rarely experienced excessive hypotension on PROCARDIA alone, this may be more common in patients on concomitant beta blocker therapy. Although not approved for this purpose, PROCARDIA and other immediate-release nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe cases of profound hypotension, myocardial infarction, and death when immediate-release nifedipine was used in this way. PROCARDIA capsules should not be used for the acute reduction of blood pressure. Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving PROCARDIA 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 PROCARDIA and a beta blocker, but the possibility that it may occur with PROCARDIA alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In PROCARDIA 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 PROCARDIA to be washed out of the body prior to surgery. 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 PROCARDIA or at the time of dosage increase. The mechanism of this effect is not established. Several well-controlled, randomized trials studied the use of immediate-release nifedipine in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. PROCARDIA capsules should not be administered within the first week or two after myocardial infarction, and they should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent). Use in Essential Hypertension PROCARDIA and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although PROCARDIA capsules have not been approved for this purpose and no properly controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. PROCARDIA capsules should not be used for the control of essential hypertension. Beta Blocker Withdrawal Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of PROCARDIA treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and PROCARDIA initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning PROCARDIA. Congestive Heart Failure Rarely, patients, usually those receiving a beta blocker, have developed heart failure after beginning PROCARDIA. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of PROCARDIA would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve. PRECAUTIONS General Hypotension Because PROCARDIA decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of PROCARDIA 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, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients treated with PROCARDIA (nifedipine). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction. 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 PROCARDIA 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. Rare instances of allergic hepatitis have been reported. PROCARDIA, 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 PROCARDIA 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 PROCARDIA administration and positivity of this laboratory test, including hemolysis, could not be determined. Although PROCARDIA 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 pre-existing chronic renal insufficiency. The relationship to PROCARDIA 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 in a non-comparative clinical trial has shown that concomitant administration of PROCARDIA 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 PROCARDIA may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination. Digitalis Since there have been isolated reports of patients with elevated digoxin levels, and since there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine). Coumarin anticoagulants There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom PROCARDIA was administered. However, the relationship to PROCARDIA 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. Other Interactions Grapefruit Juice Co-administration of nifedipine with grapefruit juice resulted in approximately a 2-fold increase in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are most likely due to inhibition of CYP 3A4 related first-pass metabolism. Co-administration of nifedipine with grapefruit juice is to be avoided. 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 were 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 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. Use in pediatric population is not recommended. Geriatric Use Although small pharmacokinetic studies have identified an increased half-life and increased Cmax and AUC (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism), clinical studies of nifedipine 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 response 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 In multiple-dose United States and foreign controlled studies 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 PROCARDIA.    PROCARDIA (%) Placebo (%) Adverse Effect (N=226) (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 Palpitation 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 most common adverse events were: Incidence Approximately 10% Cardiovascular: peripheral edema Central Nervous System: dizziness or lightheadedness Gastrointestinal: nausea Systemic: headache and flushing, weakness Incidence Approximately 5% Cardiovascular: transient hypotension Incidence 2% or Less Cardiovascular: palpitation Respiratory: nasal and chest congestion, shortness of breath Gastrointestinal: diarrhea, constipation, cramps, flatulence Musculoskeletal: inflammation, joint stiffness, muscle cramps Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties Incidence Approximately 0.5% Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia Incidence Less Than 0.5% Hematologic: thrombocytopenia, anemia, leukopenia, purpura Gastrointestinal: allergic hepatitis Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia CNS: depression, paranoid syndrome Special Senses: transient blindness at the peak of plasma level, tinnitus Urogenital: nocturia, polyuria Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia Musculoskeletal: myalgia Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of PROCARDIA therapy was associated with an increase in anginal pain, possibly due to associated hypotension. Transient unilateral loss of vision has also occurred. 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 were not different from that of the entire group of PROCARDIA (nifedipine) treated patients. (See PRECAUTIONS.) In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina pectoris (about 10% of the total patient population), 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, and 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; however, plasmapheresis may be beneficial. DOSAGE AND ADMINISTRATION The dosage of PROCARDIA needed to suppress angina and that can be tolerated by the patient must be established by titration. Excessive doses can result in hypotension. Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10–20 mg three times daily. Some patients, especially those with evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or both. In such patients, doses of 20–30 mg three or four times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg per day is not recommended. In most cases, PROCARDIA titration should proceed over a 7–14 day period so that the physician can assess the response to each dose level and monitor the blood pressure before proceeding to higher doses. If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed frequently. Based on the patient's physical activity level, attack frequency, and sublingual nitroglycerin consumption, the dose of PROCARDIA may be increased from 10 mg t.i.d. to 20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period. In hospitalized patients under close observation, the dose may be increased in 10 mg increments over four- to six-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg. Co-administration of nifedipine with grapefruit juice is to be avoided (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions). No "rebound effect" has been observed upon discontinuation of PROCARDIA. However, if discontinuation of PROCARDIA is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-Administration with Other Antianginal Drugs Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during PROCARDIA titration. See PRECAUTIONS, Drug Interactions, for information on co-administration of PROCARDIA with beta blockers or long-acting nitrates. HOW SUPPLIED PROCARDIA soft gelatin capsules are supplied in: Bottles of 100:   10 mg (NDC 0069-2600-66) The capsules should be protected from light and moisture and stored at controlled room temperature, 59° to 77°F (15° to 25°C) in the manufacturer's original container.