Cardene

Generic Name: Nicardipine
Class: Dihydropyridines
VA Class: CV200
CAS Number: 54527-84-3

Introduction

Calcium-channel blocking agent; dihydropyridine-derivative.¹

Uses for Cardene

Hypertension

Oral management of hypertension (alone or in combination with other classes of antihypertensive agents).^{1 2 3 70}

Therapy with extended-release capsules is preferred because of less frequent dosing, potentially smoother blood pressure control,⁷⁰ and concerns raised by experience with short-acting (conventional, immediate-release) nifedipine.^{35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 61 70 72 73}

One of several preferred initial therapies in hypertensive patients with a high risk of developing CAD, including those with diabetes mellitus.⁹⁴

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.⁹⁴

IV, short-term management of hypertension when oral therapy is not feasible or desirable.¹⁸

IV management of hypertensive crises (e.g., emergencies) in adults.^{18 70}

IV, rapid reduction of BP in the management of hypertensive urgencies or emergencies in pediatric patients 1–17 years of age.†⁹⁹

Angina

Management of chronic stable angina pectoris (alone or in combination with other antianginal agents).^{1 3 25}

Cardene Dosage and Administration

Administration

Administer orally^{1 2 5} or by IV infusion.^{18 22 23}

Oral Administration

Conventional Capsules

Administer orally 3 times daily.¹

Extended-release Capsules

Administer orally twice daily.²

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow, continuous IV infusion.^{18 22 23}

If administered via a peripheral vein, change infusion site every 12 hours to minimize risk of venous irritation.¹⁸

Monitor BP closely during and after completion of IV administration; avoid rapid or excessive reduction in systolic or diastolic BP.^{18 70}

Dilution

Dilute each 25 mg ampule with 240 mL of a compatible IV solution (see Solution Compatibility under Stability) to provide a solution containing 0.1 mg/mL.^{18 c}

Dosage

Available as nicardipine hydrochloride; dosage is expressed in terms of the salt.^{a b c}

Pediatric Patients

Hypertensive Urgencies or Emergencies†

Rapid Reduction of BP†

IV

Children and adolescents 1–17 years of age: 1–3 mcg/kg per minute as infusion.⁹⁹

Adults

Hypertension

Conventional Capsules

Oral

Initially, 20 mg 3 times daily.^{1 5}

Adjust dosage according to patient’s peak (approximately 1–2 hours after dosing, particularly during initiation of therapy) and trough (8 hours after dosing) BP responses, but generally no more frequently than at 3-day intervals.¹

Usual dosage is 20–40 mg 3 times daily.¹

Extended-Release Capsules

Oral

Initially, 30 mg twice daily.^{2 70}

Adjust dosage according to BP response 2–4 hours after dosing as well as just prior to next dose.²

Usual dosage range is 30–60 mg twice daily.²

Switching to Extended-Release Capsules

Oral

Total daily dose of conventional tablets not a useful guide to judging effective dose of extended-release capsules.^{2 c} However, may administer the currently effective total daily dose of conventional capsules and adjust dosage according to BP response.^{2 c}

Short-term Management with IV Therapy

IV

Initially, 5 mg/hour.^{18 70}

If target BP is not achieved, increase rate by 2.5 mg/hour every 15 minutes, up to 15 mg/hour.^{18 70}

For more rapid reduction, initially, 5 mg/hour. If the target BP is not achieved, increase rate by 2.5 mg/hour every 5 minutes, up to 15 mg/hour.^{18 70}

Following achievement of desired BP response, decrease rate to 3 mg/hour;¹⁸ adjust rate as necessary to maintain desired BP reponse.¹⁸

Conversion From Oral to IV Therapy

IV

Recommended Infusion Rates for Patients Previously Maintained on Oral Therapy.

Oral Dosage (as Conventional Capsules)	Equivalent IV Infusion Rates
20 mg every 8 hours	0.5 mg/hour
30 mg every 8 hours	1.2 mg/hour
40 mg every 8 hours	2.2 mg/hour

Hypertensive Emergency

IV

5–15 mg/hour; adjust according to BP response and tolerance.⁷⁰

Initially, reduce mean arterial BP by no more than 25% within minutes to 1 hour, then further reduce if stable toward 160/100 to 110 mm Hg within the next 2–6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.⁷⁰

If patient is stable, can further reduce BP toward normal in the next 24–48 hours.⁹⁸

Angina

Conventional Capsules

Oral

Initially, 20 mg 3 times daily.^{1 5} Adjust dosage according to patient tolerance and response at ≥3-day intervals.¹

Usual dosage range is 20–40 mg 3 times daily.¹

Prescribing Limits

Adults

Hypertension

IV

15 mg/hour.^{18 70}

Special Populations

Hepatic Impairment

Conventional capsules: Initially, 20 mg twice daily in patients with severe hepatic impairment.¹ Individualize dosage, but maintain a twice-daily dosing schedule.¹

IV infusion: Consider dosage reduction.¹⁸ Use with caution in patients with portal hypertension.¹⁸

Renal Impairment

Conventional capsules: Initially, 20 mg 3 times daily.^{1 5} Titrate dosage carefully.¹

Extended-release capsules: Initially, 30 mg twice daily.² Titrate dosage carefully.²

IV infusion: Titrate dosage carefully.¹⁸

Geriatric Patients

Cautious dosing recommended.^{a b} For conventional and extended-release capsules, initiate therapy at low end of dosage range.^{20 68}

Cautions for Cardene

Contraindications

• 
  

  Known hypersensitivity to nicardipine or any ingredient in the formulation.^{1 2 18}

  
  


• 
  

  Advanced aortic stenosis, since reduction in diastolic pressure may worsen myocardial oxygen balance.^{1 2 18}

  
  

Warnings/Precautions

Warnings

Increased Angina

Increased frequency, duration, and severity of angina upon initiation or dosage increase of calcium channel blockers.^{1 2 18}

CHF

Use with caution in patients with CHF or substantial left ventricular dysfunction, especially in those receiving concomitant β-adrenergic blocking agents.^{1 2 18}

β-Blocker Withdrawal

Taper dosage of β-adrenergic blocking agent, preferably over 8–10 days before initiation of nicardipine.^{1 2 18} Nicardipine is not a β-adrenergic blocking agent and offers no protection against abrupt withdrawal of these agents.^{1 2 18}

General Precautions

Hypotension

Possible symptomatic hypotension from decreased peripheral resistance.^{1 2 18} Use with caution in patients with acute cerebral infarction or hemorrhage; avoid systemic hypotension in these patients.^{1 2 18}

Monitor BP carefully, especially during initiation of therapy or upward adjustment of dosage.¹

Pheochromocytoma

Limited clinical experience in patients with hypertension associated with pheochromocytoma.¹⁸ Use with caution.¹⁸

Specific Populations

Pregnancy

Category C.^{1 2 18}

Lactation

Distributed into milk in high concentrations in rats.^{1 2 18} Use not recommended.^{1 2 18}

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 2 18}

Use with caution for rapid reduction of BP in pediatric patients 1–17 years of age†; may cause reflex tachycardia.⁹⁹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.^{a b} Select dosage with caution; initiate dosage at lower end of recommended range.^{a b}

Hepatic Impairment

Use with caution in patients with hepatic impairment or reduced hepatic blood flow; dosage adjustments recommended.^{1 2 18 24} (See Hepatic Impairment under Dosage and Administration.)

Use of extended-release capsules has not been studied in patients with severe hepatic impairment.²

Renal Impairment

Use with caution; careful dosage titration recommended.^{1 2 18} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

With oral therapy, pedal edema, dizziness, headache, asthenia, flushing, increased angina, vasodilation, palpitation.^{a b}

With IV therapy, headache, hypotension, nausea/vomiting, tachycardia.^c

Interactions for Cardene

Specific Drugs

Drug	Interaction	Comments
Antacids (magnesium hydroxide)	Pharmacokinetic interaction unlikely1 2 18
β-Adrenergic blockers (e.g., propranolol)	Pharmacokinetic interaction (e.g., effect on plasma protein binding of nicardipine) unlikely1 2 18
Cimetidine	Increased plasma nicardipine concentrations1 2 18	Monitor carefully1 2 18
Cyclosporine	Increased plasma cyclosporine concentrations1 2 18	Monitor plasma cyclosporine concentrations closely and adjust dosage accordingly1 2 18
Digoxin	Potential for increased plasma digoxin concentrations1 2 18	Monitor serum digoxin concentrations1 2 18
Dipyridamole	No effect on plasma protein binding of nicardipine1 2 18
Fentanyl	Potential for severe hypotension with concomitant use of a β-adrenergic blocker and a calcium channel blocker1 2 18	Increase circulating fluid volume if hypotension occurs1 2 18
Furosemide	No effect on plasma protein binding of nicardipine1 2 18
Naproxen	No effect on plasma protein binding of nicardipine1 2 18
Quinidine	No effect on plasma protein binding of nicardipine1 2 18
Warfarin	No effect on plasma protein binding of nicardipine1 2 18

Cardene Pharmacokinetics

Absorption

Bioavailability

Completely absorbed from the GI tract following oral administration; peak plasma concentrations of conventional and extended-release capsules are attained within 0.5–2 and 1–4 hours, respectively.^{1 2}

Minimum plasma levels of equivalent doses of conventional and extended-release capsules are similar.²

Bioavailability of conventional capsules is about 35%;^{1 2} extended-release capsules have a slightly lower bioavailability, except at the highest doses.²

Food

High-fat meal decreases bioavailability of conventional and extended-release capsules.^{1 2}

Special Populations

In patients with severe hepatic impairment, peak plasma concentrations and AUC increased by 1.8 and 4-fold, respectively, and terminal half-life prolonged to 19 hours.^{1 2}

In patients with moderate renal impairment, peak plasma concentrations and AUC increased by 2- to 3-fold following administration of conventional or extended-release capsules.^{1 2}

Distribution

Extent

Distributed into milk in rats.^{1 2}

Plasma Protein Binding

>95%.^{1 2 18}

Elimination

Metabolism

Extensively metabolized in the liver.^{1 2 18}

Elimination Route

Excreted in urine (49–60%) and feces (35–43%).^{1 2 18}

Half-life

Multi-phasic; terminal elimination half-life is 8.6 and 14.4 hours following oral and IV administration, respectively.^{1 2 18}

Stability

Storage

Oral

Conventional Capsules and Extended-release Capsules

Light resistant containers at 15–30°C.^{a b}

Parenteral

Injection

20–25°C; protect from light.^c Avoid exposure to increased temperatures.^c

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in sodium chloride 0.45% or 0.9%
Dextrose 5% in water with potassium chloride 0.3%
Sodium chloride 0.9%
Incompatible
Sodium bicarbonate 5%
Variable
Dextrose 5% in Ringer’s injection, lactated
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.45%

Drug Compatibility^HID

Admixture Compatibility

Compatible
Potassium chloride 40 mEq

Y-Site CompatibilityHID

Compatible
Amikacin sulfate
Aminophylline
Aztreonam
Butorphanol tartrate
Calcium gluconate
Cefazolin sodium
Ceftizoxime sodium
Chloramphenicol sodium succinate
Cimetidine HCl
Clindamycin phosphate
Co-trimoxazole
Dextran 40 in dextrose 5%
Diltiazem HCl
Dobutamine HCl
Dopamine HCl
Enalaprilat
Epinephrine HCl
Erythromycin lactobionate
Esmolol HCl
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Gentamicin sulfate
Hetastarch in sodium chloride 0.9%
Hydrocortisone sodium succinate
Hydromorphone HCl
Labetalol HCl
Lidocaine HCl
Linezolid
Lorazepam
Magnesium sulfate
Methylprednisolone sodium succinate
Metronidazole
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nafcillin sodium
Nitroglycerin
Norepinephrine bitartrate
Normosol R
Penicillin G potassium
Plasma-Lyte A
Potassium chloride
Potassium phosphates
Ranitidine HCl
Sodium acetate
Sodium nitroprusside
Tobramycin sulfate
Vancomycin HCl
Vecuronium bromide
Incompatible
Ampicillin sodium
Ampicillin sodium-sulbactam sodium
Cefepime HCI
Furosemide
Lansoprazole
Thiopental sodium
Variable
Ceftazidime
Heparin sodium

ActionsActions

• 
  

  Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium calcium concentrations.^{a b c}

  
  


• 
  

  Peripheral arterial vasodilator; acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and BP.^{a b c}

  
  

Advice to Patients

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{1 2 18}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2 18}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 2 18} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nicardipine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	20 mg*	Cardene	Roche
			Nicardipine Hydrochloride	Mylan, IVAX, Par, Teva
		30 mg*	Cardene	Roche
			Nicardipine Hydrochloride	Mylan, IVAX, Par, Teva
	Capsules, extended-release	30 mg	Cardene SR	Roche
		45 mg	Cardene SR	Roche
		60 mg	Cardene SR	Roche
Parenteral	For injection, concentrate, for IV infusion	2.5 mg/mL	Cardene I.V. (with sorbitol)	PDL Biopharma

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cardene 20MG Capsules (ROCHE): 90/$69.99 or 270/$189.96

Cardene 30MG Capsules (ROCHE): 90/$99.99 or 270/$282.96

Cardene SR 30MG 12-hr Capsules (EKR THERAPEUTICS): 60/$105.99 or 180/$305.98

Cardene SR 45MG 12-hr Capsules (EKR THERAPEUTICS): 60/$169.98 or 180/$499.97

NiCARdipine HCl 20MG Capsules (MYLAN): 90/$45.99 or 270/$120.97

NiCARdipine HCl 30MG Capsules (TEVA PHARMACEUTICALS USA): 90/$32.99 or 270/$81.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Syntex Laboratories, Inc. Cardene (nicardipine hydrochloride) capsules prescribing information. Palo Alto CA; 1992 Jul.

2. Syntex Laboratories, Inc. Cardene SR (nicardipine hydrochloride) sustained release capsules prescribing information. Palo Alto CA; 1992 Jan.

3. Freedman DD, Waters DD. Second generation dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications. Drugs. 1987; 34:578-98. [IDIS 236664] [PubMed 3319491]

4. Murdoch D, Heel RC. Amlodipine : a review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in cardiovascular disease. Drugs. 1991; 41:478-505. [PubMed 1711448]

5. Sorkin EM, Clissold SP. Nicardipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders. Drugs. 1987; 33:296-345. [IDIS 236761] [PubMed 3297616]

6. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

7. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

8. Syntex Laboratories, Inc, Palo Alto, CA: (personal observations).

9. Sandoz Pharmaceuticals Corp. DynaCirc (isradipine) capsules prescribing information. East Hanover, NJ; 1992 Jun.

10. Lopez LM, Santiago TM. Isradipine—another calcium-channel blocker for the treatment of hypertension and angina. Ann Pharmacother. 1992; 26:789-99. [IDIS 298260] [PubMed 1535246]

11. Fitton A, Benfield P. Isradipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs. 1990; 40:31-74. [PubMed 2143980]

12. Walton T, Symes LR. Felodipine and isradipine: new calcium-channel blocking agents for the treatment of hypertension. Clin Pharm. 1993; 12:261-75. [IDIS 311530] [PubMed 8458178]

13. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

14. Prisant LM, Carr AA, Nelson EB et al. Isradipine vs propranolol in hydrochlorothiazide-treated hypertensives: a multicenter evaluation. Arch Intern Med. 1989; 149:2453-7. [IDIS 260612] [PubMed 2530945]

15. Anon. Isradipine for hypertension. Med Lett Drugs Ther. 1991; 33:51-4. [PubMed 1827655]

16. Alderman MH. Which antihypertensive drugs first—and why! JAMA. 1992; 267:2786-7. Editorial.

17. Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med. 1993; 153:149-52. [PubMed 8422205]

18. PDL Biopharma. Cardene I.V. (nicardipine hydrochloride) prescribing information. Philadelphia PA; 2006 Jan.

19. Fagan TC, Tyler ED, Reitman MA et al. Sustained-release nicardipine in mild-to-moderate hypertension. Chest. 1993; 104:427-33. [IDIS 319803] [PubMed 8339631]

20. Frampton JE, Faulds D. Nicardipine. A review of its pharmacology and therapeutic efficacy in older patients. Drugs Aging. 1993; 3:165-87. [PubMed 8477149]

21. Bosch X, Sobrino J, Lopez-Soto A et al. Parotitis due to nicardipine. BMJ. 1992; 304:882. [IDIS 294759] [PubMed 1392752]

22. IV Nicardipine Study Group. Efficacy and safety of intravenous nicardipine in the control of postoperative hypertension. Chest. 1991; 99:393-8. [IDIS 283340] [PubMed 1989801]

23. Wallin JD, Fletcher E, Ram VS et al. Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial. Arch Intern Med. 1989; 149:2662-9. [IDIS 264762] [PubMed 2688586]

24. Razak TA, McNeil JJ, Sewel RB et al. The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine. Clin Pharmacol Ther. 1990; 47:463-9. [IDIS 267303] [PubMed 2328554]

25. Sklar J, Dennish GW III, Glode J et al. Usefulness of nicardipine as monotherapy for chronic, stable angina. Am J Cardiol. 1989; 63:1203-7. [IDIS 255507] [PubMed 2711990]

26. Eicher JC, Chalopin JM, Tanter Y et al. Nicardipine and urinary retention. JAMA. 1987; 258:3388. [IDIS 236430] [PubMed 3682133]

27. Dubois C, Blanchard D. Efficacy and safety of nicardipine in 29,104 patients with hypertension. Clin Ther. 1989; 11:452-60. [PubMed 2673515]

28. Nami R, Caruso D, Dormi A et al. Efficacy and tolerability of nicardipine slow release and enalapril in elderly hypertensive patients: results of a multicenter study. Curr Ther Res. 1993; 54:221-31.

29. Kubota K, Pearce GL, Inman WHW. Vasodilation-related adverse events in diltiazem and dihydropyridine calcium antagonists studied by prescription-event monitoring. Eur J Clin Pharmacol. 1995; 48:1-7. [IDIS 347118] [PubMed 7621840]

30. Jannet D, Carbonne B, Sebban E et al. Nicardipine versus metoprolol in the treatment of hypertension during pregnancy: a randomized comparative trial. Obstet Gynecol. 1994; 84:354-9. [IDIS 334071] [PubMed 8058230]

31. Carbonne B, Jannet D, Touboul C et al. Nicardipine treatment of hypertension during pregnancy. Obstet Gynecol. 1993; 81:908-14. [IDIS 314996] [PubMed 8497354]

32. Narváez M, Figueras A, Capellá D et al. Tinnitus with calcium-channel blockers. Lancet. 1994; 343:1229-30.

33. Agre K. An overview of the safety and efficacy of nicardipine in clinical trials. Am J Cardiol. 1987; 59:31J-5J. [IDIS 313618] [PubMed 3300239]

34. Ahmad S. Nicardipine-induced hyperglycemia. Am Fam Physician. 1992; 45:449,452. [PubMed 1739035]

35. Glasser SP, Clark PI, Lipicky RJ et al. Exposing patients with chronic, stable, exertional angina to placebo periods in drug trials. JAMA. 1991; 265:1550- 4. [PubMed 1671885]

36. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.

37. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.

38. Anon. NHLBI panel stands by JNC V in response to Circulation CCB article; AIM report supports use of beta blockers for prevention of sudden cardiac death. F-D-C Rep. 1995; 57(Sep 4):3-4.

39. American Heart Association. Public advisory statement on calcium channel blocker drugs. Dallas, TX; 1995 Aug 28.

40. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995; 274:620-5. [IDIS 352203] [PubMed 7637142]

41. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of incident myocardial infarction associated with anti- hypertensive drug therapies. Circulation. 1995; 91:925.

42. Buring JE, Glynn RJ, Hennekens CH. Calcium channel blockers and myocardial infarction: a hypothesis formulated but not yet tested. JAMA. 1995; 274:654-5. [IDIS 352205] [PubMed 7637148]

43. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995; 92:1326-31. [IDIS 353358] [PubMed 7648682]

44. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation. 1995; 92:1068-73. [IDIS 353353] [PubMed 7648646]

45. Kloner RA. Nifedipine in ischemic heart disease. Circulation. 1995; 92:1074-8. [IDIS 353354] [PubMed 7648647]

46. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation. 1995; 92:1079-82. Editorial.

47. Lenfant C. The calcium channel blocker scare: lessons for the future. Circulation. 1995; 91:2855-6. [PubMed 7796490]

48. Habib GB. Are calcium antagonists harmful in hypertensive patients? Distinguishing hype from reality. Chest. 1995; 108:3-5. [IDIS 351406] [PubMed 7606987]

49. Horton R. Spinning the risks and benefits of calcium antagonists. Lancet. 1995; 346:586-7. [IDIS 353102] [PubMed 7650997]

50. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol. 1991; 67:1295-7. [IDIS 284079] [PubMed 2035457]

51. Egstrup K, Andersen PE Jr. Transient myocardial ischemia during nifedipine therapy in stable angina pectoris, and its relation to coronary collateral flow and comparison with metoprolol. Am J Cardiol. 1993; 71:177-83. [IDIS 308552] [PubMed 8421980]

52. Wagenknecht LE, Furberg CD, Hammon JW et al. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ. 1995; 310:776-7. [IDIS 345035] [PubMed 7711582]

53. Miles Inc. American Heart Association, Dr. Psalty and Miles Inc. release statements qualifying possible risks of calcium channel blockers. West Haven, CT; 1995 Mar 15. Press release.

54. Dear healthcare professional letter regarding calcium-channel blockers and increased risk of heart attack. Chicago:Searle. 1995 Mar 17.

55. McClellan K. Unexpected results from MIDAS in atherosclerosis. Inpharma Wkly. 1994; Apr 9:4.

56. Anon. Groups act to dispel concerns about calcium-channel blockers. Am J Health- Syst Pharm. 1995; 52:1154,1158. [PubMed 7656105]

57. Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation. 1991; 84:2598-600. [IDIS 295953] [PubMed 1959210]

58. Messerli FH. Case-control study, meta-analysis, and bouillabaisse: putting the calcium antagonist scare into context. Ann Intern Med. 1995; 123:888-9. [IDIS 356631] [PubMed 7486476]

59. Reviewers’ comments (personal observations).

60. Pratt Pharmacueticals. Procardia (nifedipine) capsules prescribing information (dated 1993 Feb). In: Physicians’ desk reference. 49th ed. Montvale, NJ: Medical Economics Company Inc; 1995:1906-7.

61. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. BMJ. 1989; 299:1187-92. [IDIS 260789] [PubMed 2513047]

62. Kitler ME. The changing face of hypertension and antihypertensive agents. Drugs Aging. 1996; 8:5-11. [PubMed 8785469]

63. Parker BM, Cusack BJ, Vestal RE. Pharmacokinetic optimisation of drug therapy in elderly patients. Drugs Aging. 1995; 7:10-8. [PubMed 7579777]

64. Kvasnicka J, Flack JM, Grimm RH. Treatment of hypertension in the presence of coexisting medical conditions. Drugs Aging. 1994; 4:304-12. [PubMed 8019053]

65. Kelly JG, O’Malley K. Calcium antagonists in the elderly. Drugs Aging. 1993; 3:400-7. [PubMed 8241605]

66. Burris JF. Practical considerations in treating the elderly hypertensive patient. Am J Med. 1991; 90(Suppl 4B):28-31S.

67. O’Malley K, Cox JP, O’Brien E. Choice of drug treatment for elderly hypertensive patients. Am J Med. 1991; 90(Suppl 3A):27-33S.

68. Food and Drug Administration. Specific requirements on content and format of labeling for human prescrption drugs; proposed addition of ”geriatric use“ subsection in the labeling; proposed rule (Docket No. 89N-0474). Fed Regist. 1990; 55:46134-7.

69. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant in the interaction? Clin Pharmcokinet. 1994; 26:91-8.

70. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

71. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [PubMed 8622249]

72. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA. 1997; 277:739-45. [IDIS 380501] [PubMed 9042847]

73. American College of Cardiology and American Heart Association. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996; 28:1328-428. [IDIS 376249] [PubMed 8890834]

74. Staessen JA, Fagard R, Thijs L et al. for the Systolic Hypertension-Europe (Syst-Eur) Trial Investigators. Morbidity and mortality in the placebo-controlled European Trial on Isolated Systolic Hypertension in the Elderly. Lancet. 1997; 350:757-64. [IDIS 392056] [PubMed 9297994]

75. Velussi M, Brocco E, Frigato F et al. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes. 1996; 45:216-22. [IDIS 362953] [PubMed 8549868]

76. Estacio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998; 338:645-52. [IDIS 400553] [PubMed 9486993]

77. Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive patients with diabetes. Lancet. 1998; 351:689-90. [IDIS 409001] [PubMed 9504510]

78. Tatti P, Pahor M, Byington RP et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) in patients

79. Byington RP, Craven TE, Furberg CD et al. Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events. Lancet. 1997; 350:1075-6. [IDIS 393279] [PubMed 10213554]

80. Alderman M, Madhavan S, Cohen H. Calcium antagonists and cardiovascular events in patients with hypertension and diabetes. Lancet. 1998; 351:216-7. [IDIS 398935] [PubMed 9449897]

81. Josefson D. Infarction risk found with calcium channel blocker. BMJ. 1998; 316:797.

82. Cutler JA. Calcium-channel blockers for hypertension—uncertainty continues. N Engl J Med. 1998; 338:679-81. [IDIS 400554] [PubMed 9486999]

83. Bayer, West Haven, CT: Personal communication.

84. Bakris GL, Copley JB, Vicknair N et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int. 1996; 50:1641-50. [PubMed 8914031]

85. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Phramacokinet. 1997; 33:103-21.

86. Roller L. Drugs and grapefruit juice. Clin Pharmacol Ther. 1998; 63:87. [IDIS 398865] [PubMed 9465845]

87. Spence JD. Drugs and grapefruit juice. Clin Pharmacol Ther. 1998; 63:87-8. [IDIS 398865] [PubMed 9465845]

88. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

89. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

90. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

91. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site.

92. Appel LJ. The verdict from ALLHAT—thiazi