Ted -- A Testimonial Before The Results Are In
NOTES Related To Ted's Story

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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 or 20 mg nifedipine. Inert ingredients in the formulations 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.

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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.

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

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.

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.

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. It 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.

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 (5-10mm 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.

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.

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.

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.)

Known hypersensitivity reaction to PROCARDIA.

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.

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.

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.

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.

Rarely, patients, usually 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.

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.

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 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.

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

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

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

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.

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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

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.

In multiple-dose U.S. 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.

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:

Cardiovascular: peripheral edema

Central Nervous System: dizziness or lightheadedness

Gastrointestinal: nausea

Systemic: headache and flushing, weakness

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Cardiovascular: transient hypotension

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

Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose),

erythromelalgia

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.

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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 (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.

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.

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.

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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.

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.

Sublingual nitroglycerin may be taken as required for the control of acute manifestations of

for information on co-administration of PROCARDIA with beta blockers or long-acting nitrates.

PROCARDIA® soft gelatin capsules are supplied in:

Bottles of 100: 10 mg (NDC 0069-2600-66)

20 mg (NDC 0069-2610-66)

Bottles of 300: 10 mg (NDC 0069-2600-72)

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.

Division of Pfizer Inc, NY, NY 10017

Printed in U.S.A.

69-4990-00-1 Revised September 2000