Generic Name: NIFEDIPINE
Brand Name: Nifedipine
- Substance Name(s):
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Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines.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.
Gastointestinal Obstruction Requiring Surgery There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of Nifedipine Extended-release Tablets.
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 Nifedipine Extended-release Tablets 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., H 2 -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.
Drug Interactions Beta-adrenergic blocking agents (see INDICATIONS AND USAGE and WARNINGS .) Experience in over 1400 patients with nifedipine 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.
Nifedipine is metabolized by CYP3A4.
Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%.
Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy.
CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when co-administered.
Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications.
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 Nifedipine Extended-release Tablets.
The main effects of ingestion of approximately 4800 mg of Nifedipine Extended-release Tablets 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 nifedipine 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 nifedipine 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.
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, C 17 H 18 N 2 O 6, 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 346.33.
Nifedipine Extended-release Tablet is formulated as a once-a-day extended-release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine.
Inert ingredients in the formulations are: black iron oxide; cellulose acetate; colloidal silicon dioxide; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polyethylene oxide; polysorbate; povidone; propylene glycol; red ferric oxide; sodium chloride; titanium dioxide; triacetin.
Chemical Structure System Components and Performance Nifedipine Extended-release Tablet is similar in appearance to a conventional tablet.
It consists, however, of a semipermeable membrane surrounding an osmotically active drug core.
As water from the gastrointestinal tract enters the tablet, pressure increases in the core of the tablet, releasing drug through the precision laser-drilled tablet orifice in the one side of the tablet.
Nifedipine 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.
Nifedipine Extended-release Tablet depends for its action on the existence of an osmotic gradient between the contents of the tablet 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.
USP Drug Release Test 5.
Nifedipine Extended-release Tablets 30 mg are round, biconvex, pink coated tablets imprinted with “KU 260” in black ink.
They are supplied as follows: Bottles of 30 Tablets NDC 68645-512-54 Nifedipine Extended-release Tablets 60 mg are round, biconvex, pink coated tablets imprinted with “KU 261” in black ink.
They are supplied as follows: Bottles of 30 Tablets NDC 68645-513-54 Store at 20°-25°C (68°-77°F) (See USP Controlled Room Temperature).
Protect from moisture, humidity, and light.
For Medical Information Contact: Medical Affairs Department Phone: 1-844-834-0530 Distributed by: Lannett Company, Inc.
Philadelphia, PA 19136 Distributed By: Wal-Mart Bentonville, AR 72716 Packaged By: Legacy Pharmaceutical Packaging LLC Earth City, MO 63045 CIA70797K Rev.
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
Vasospastic Angina Nifedipine Extended-release Tablet 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.
Nifedipine Extended-release Tablet 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.
Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine Extended-release Tablet 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 ).
Hypertension Nifedipine Extended-release Tablet is indicated for the treatment of hypertension, to lower blood pressure.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Nifedipine Extended-release Tablet.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.
Many patients will require more than one drug to achieve blood pressure goals.
For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.
The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.
Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).
These considerations may guide selection of therapy.
Nifedipine Extended-release Tablet may be used alone or in combination with other antihypertensive agents.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
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 (5 to 50 times) than the maximum recommended human dose of 120 mg/day.
On a mg/m 2 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/m 2 basis.
There are no adequate and well-controlled studies in pregnant women.
Nifedipine Extended-release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk.
INFORMATION FOR PATIENTS
Information for Patients Nifedipine 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 Nifedipine Extended-release Tablets, 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.
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.
Nifedipine 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 nifedipine capsules alone or in combination with other antianginal medications may be safely switched to Nifedipine Extended-release Tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d.
of nifedipine capsules may be changed to 90 mg once daily of Nifedipine 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.
Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions ).
No “rebound effect” has been observed upon discontinuation of Nifedipine 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 Nifedipine Extended-release Tablets 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.