Amlodipine

Norvasc is the brand name for amlodipine besylate, a prescription drug used to treat hypertension, or high blood pressure.

Norvasc is also used to treat coronary artery disease (CAD) in patients without heart failure, and certain types of angina (chest pain) from CAD, such as activity- and stress-induced angina (chronic stable angina), and angina that occurs at rest (Prinzmetal’s angina).

Taken regularly, Norvasc can control angina, but it doesn't stop chest pain after it has already begun.

The drug can also lower a person's risk of cardiovascular events related to high blood pressure, such as strokes and heart attacks.

Norvasc belongs to a class of drugs called calcium channel blockers, which block the flow of calcium into heart muscles and the muscles along the walls of blood vessels.

Because the contraction of these muscles depends on calcium, Norvasc relaxes and widens blood vessels, thereby improving blood flow.

Doctors also sometimes prescribe Norvasc "off-label" for the treatment of cluster headaches, migraines, Raynaud's syndrome (a blood vessel disorder), and congestive heart failure.

Manufactured by Pfizer, Norvasc was first approved by the Food and Drug Administration (FDA) in 1987.

In the early 1990s, researchers conducted the so-called PRAISE study, which was backed by Pfizer, to determine if Norvasc could help reduce the risk of death in people with severe heart failure.

Though the study found little overall benefits to severe heart failure patients, it suggested that Norvasc might prolong the life of a subgroup of people with heart failure from non-ischemic cardiomyopathy (cardiac muscle damage not associated with low blood supply to the coronary arteries).

To investigate this possibility, Pfizer-sponsored the PRAISE-2 study, which found no benefit to the subgroup in the PRAISE-1 trial and was presented at a conference in 2000.

However, results of the study weren't published in an academic journal until 2013, leading some experts to question whether Pfizer intentionally delayed publication to prevent the data and findings from being publicly available.

Norvasc Warnings

People with a known sensitivity to amlodipine should not take Norvasc.

Though Norvasc is used to treat angina, worsening chest pain and heart attacks can develop after starting or increasing your dose of the drug — this is especially true for people with severe obstructive coronary artery disease.

Norvasc can also cause symptomatic hypotension (low blood pressure), particularly in people with a heart valve problem called aortic stenosis.

Before starting Norvasc, let your doctor know if you ever had heart disease or liver problems, as you may require a different course of Norvasc treatment.

Pregnancy and Norvasc

Norvasc poses a possible hazard to unborn infants.

Animal studies have shown that Norvasc increases the risk of death of fetuses in utero, decreases litter size, and prolongs both pregnancy and labor duration, but there have been no adequate and well-controlled studies in pregnant women.

The drug should therefore only be used during pregnancy if the benefits to the mother outweigh the risks to the unborn child.

Women who are breastfeeding should not use Norvasc because it's unknown if the drug is excreted in breast milk.

Contraindications

Hypersensitivity

Cautions

Congestive heart failure (CHF)

Persistent progressive dermatologic reactions

Symptomatic hypotension with or without syncope possible, particularly with severe aortic stenosis; because of gradual onset of action, acute hypotension unlikely

Worsening of angina and acute myocardial infarction (MI) can develop after dose is started or increased, particularly with severe obstructive CAD

Peripheral edema may develop within 2-3 weeks of starting therapy

Use with caution in patients with hypertrophic cardiomyopathy; reduction in afterload may worsen symptoms associated with this condition

May reduce coronary perfusion and result in ischemia in patients with severe aortic stenosis; use caution

Extensively metabolized by liver; titrate dose slowly with severe hepatic impairment

Initiate at lower dose in the elderly

Titrate dose every 7-14 days on a given dose; peak antihypertensive effect is delayed

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction; monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment

Amlodipine may increase systemic exposure of cyclosporine or tacrolimus when co-administered; frequent monitoring of trough blood levels of cyclosporine and tacrolimus recommended; adjust dose when appropriate

Amlodipine is a prescription medication used to treat high blood pressure and chest pain (angina). Amlodipine belongs to a group of drugs called calcium channel blockers, which help relax blood vessels. This makes it easier for the heart to pump blood.

This medication comes in tablet form and is usually taken once a day, with or without food.

Common side effects include headache, swelling of legs or ankles, tiredness, and nausea.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For amlodipine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to amlodipine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of amlodipine to treat high blood pressure in children younger than 6 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amlodipine in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving amlodipine.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking amlodipine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using amlodipine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Atazanavir
• Ceritinib
• Clarithromycin
• Clopidogrel
• Conivaptan
• Cyclosporine
• Dantrolene
• Digoxin
• Domperidone
• Droperidol
• Eliglustat
• Idelalisib
• Lacosamide
• Netupitant
• Piperaquine
• Simvastatin
• Tacrolimus
• Tegafur
• Telaprevir

Using amlodipine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Indinavir

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of amlodipine. Make sure you tell your doctor if you have any other medical problems, especially:

• Angina (chest pain) or
• Heart attack, acute or
• Heart or blood vessel disease (e.g., coronary artery disease) or
• Hypotension (low blood pressure)—Use with caution. May make these conditions worse.

• Heart disease or other heart problems (e.g., aortic stenosis)—Use with caution. The blood pressure-lowering effects of amlodipine may be increased.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

It is very important that your doctor check your progress at regular visits to make sure amlodipine is working properly. Blood tests may be needed to check for unwanted effects. a

Dizziness, lightheadedness, or fainting may also occur if you exercise or if the weather is hot. Heavy sweating can cause loss of too much water and result in low blood pressure. Use extra care during exercise or hot weather.

If you have been using amlodipine regularly for several weeks, do not suddenly stop using it. Stopping suddenly may cause your chest pain or high blood pressure to come back or get worse. Check with your doctor for the best way to reduce gradually the amount you are taking before stopping completely.

Chest pain resulting from exercise or physical exertion is usually reduced or prevented by amlodipine. This may tempt you to be too active. Make sure you discuss with your doctor a safe amount of exercise for your medical problem.

After taking a dose of amlodipine you may get a headache that lasts for a short time. This should become less noticeable after you have taken amlodipine for a while. If this effect continues, or if the headaches are severe, check with your doctor.

In some patients, tenderness, swelling, or bleeding of the gums may appear soon after treatment with amlodipine is started. Brushing and flossing your teeth carefully and regularly and massaging your gums may help prevent this. See your dentist regularly to have your teeth cleaned. Check with your doctor or dentist if you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums.

Do not take other medicines unless they have been discussed with your doctor. This especially includes over-the-counter (nonprescription) medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, since they may increase your blood pressure.

• It is used to treat high blood pressure.
• It is used to treat chest pain or pressure.
• Do not use amlodipine to treat sudden chest pain. It will not help. Talk with your doctor.
• It may be given to you for other reasons. Talk with the doctor.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about amlodipine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about amlodipine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using amlodipine.

Review Date: October 4, 2017

Hypertension

Amlodipine besylate tablets are 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 Amlodipine besylate tablets.

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.

Amlodipine besylate tablets may be used alone or in combination with other antihypertensive agents.

Coronary Artery Disease (CAD)

Chronic Stable Angina

Amlodipine besylate tablets are indicated for the symptomatic treatment of chronic stable angina. Amlodipine besylate tablets may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinzmetal’s or Variant Angina)

Amlodipine besylate tablets are indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine besylate tablets may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction < 40%, Amlodipine besylate tablets are indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine besylate has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with Amlodipine besylate was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Amlodipine besylate were of mild or moderate severity. In controlled clinical trials directly comparing Amlodipine besylate (N = 1730) at doses up to 10 mg to placebo (N = 1250), discontinuation of Amlodipine besylate because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with Amlodipine treatment as shown in the following table:

The following events occurred in < 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.

Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,1 epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Amlodipine besylate therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)], the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of Amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and Amlodipine.

Amlodipine besylate has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. 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. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Amlodipine. Within the physiologic pH range, Amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which Amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, Amlodipine besylate reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: Amlodipine besylate has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of Amlodipine besylate in vasospastic (Prinzmetal’s or variant) angina.

Pharmacodynamics

Hemodynamics: Following administration of therapeutic doses to patients with hypertension, Amlodipine besylate produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of Amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of Amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Amlodipine besylate is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of Amlodipine besylate resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Amlodipine besylate have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Amlodipine besylate has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects: Amlodipine besylate does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving Amlodipine besylate and concomitant beta-blockers. In clinical studies in which Amlodipine besylate was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, Amlodipine besylate therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Drug interactions

Sildenafil: When Amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)].

Pharmacokinetics

After oral administration of therapeutic doses of Amlodipine besylate, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Amlodipine besylate is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of Amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Elderly patients and patients with hepatic insufficiency have decreased clearance of Amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.

Drug interactions

In vitro data indicate that Amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Impact of other drugs on Amlodipine

Coadministered cimetidine, magnesium- and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to Amlodipine.

CYP3A inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg Amlodipine in elderly hypertensive patients resulted in a 60% increase in Amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change Amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of Amlodipine to a greater extent [see Drug Interactions (7.1)].

Impact of Amlodipine on other drugs

Coadministered Amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of Amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7.2)].

Cyclosporine: A prospective study in renal transplant patients (N = 11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with Amlodipine [see Drug Interactions (7.2)].

Tacrolimus: A prospective study in healthy Chinese volunteers (N = 9) with CYP3A5 expressers showed a 2.5 to 4 fold increase in tacrolimus exposure when concomitantly administered with Amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N = 6). However, a 3 fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of Amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)].

Pediatric Patients

Sixty-two hypertensive patients aged 6 to 17 years received doses of Amlodipine besylate between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Effects in Hypertension

Adult Patients

The antihypertensive efficacy of Amlodipine besylate has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on Amlodipine besylate and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24 hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.

Pediatric Patients

Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to Amlodipine besylate 2.5 mg or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults.

Effects in Chronic Stable Angina

The effectiveness of 5 to 10 mg/day of Amlodipine besylate in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 Amlodipine besylate, 354 placebo) with chronic stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for Amlodipine besylate, 10 mg, and averaged 7.9% (38 sec) for Amlodipine besylate, 5 mg. Amlodipine besylate, 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of Amlodipine besylate in angina patients has been demonstrated over long-term dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Effects in Vasospastic Angina

In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, Amlodipine besylate therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p < 0.01). Two of 23 Amlodipine besylate and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

Effects in Documented Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to Amlodipine besylate (5 to 10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD.

CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and without heart failure or an ejection fraction < 40%. Patients (76% males, 89% Caucasian, 93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either Amlodipine besylate (5 to 10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the Amlodipine besylate and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540 to 0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (see Table 1). Effects in various subgroups are shown in Figure 2.

In an angiographic substudy (n = 274) conducted within CAMELOT, there was no significant difference between Amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular ultrasound.

Figure 1 - Kaplan-Meier Analysis of Composite Clinical Outcomes for Amlodipine Besylate Versus Placebo

Figure 2 - Effects on Primary Endpoint of Amlodipine Besylate Versus Placebo Across Sub-Groups

Table 1 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between Amlodipine besylate and placebo.

Studies in Patients With Heart Failure

Amlodipine besylate has been compared to placebo in four 8 to 12 week studies of patients with NYHA Class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of Amlodipine besylate, 5 to 10 mg in 1153 patients with NYHA Classes III (n = 931) or IV (n = 222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, Amlodipine besylate had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Amlodipine besylate and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n = 827) or Amlodipine besylate (n = 827) and followed them for a mean of 33 months. There was no statistically significant difference between Amlodipine besylate and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on Amlodipine besylate). With Amlodipine besylate there were more reports of pulmonary edema.

(am LOE di peen)

Antihypertensive effect: Significant reductions in blood pressure at 24 to 48 hours after first dose; slight increase in heart rate within 10 hours of administration may reflect some vasodilating activity (Donnelly 1993)

Time to Peak

Plasma: 6 to 12 hours

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of AmLODIPine. Management: Reduce amlodipine dose by at least 50% and monitor for increased amlodipine effects (eg, hypotension) if an antihepaciviral combination product is initiated. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Atosiban: Calcium Channel Blockers may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Monitor therapy

CarBAMazepine: May increase the metabolism of Calcium Channel Blockers (Dihydropyridine). Management: Consider calcium channel blocker (CCB) dose adjustments or alternative therapy in patients receiving concomitant carbamazepine. Nimodipine Canadian labeling contraindicates concurrent use with carbamazepine. Consider therapy modification

Ceritinib: May increase the serum concentration of CYP3A4 Substrates. Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of AmLODIPine. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of AmLODIPine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Calcium Channel Blockers. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Efavirenz: May decrease the serum concentration of Calcium Channel Blockers. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fluconazole: May increase the serum concentration of Calcium Channel Blockers. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of AmLODIPine. Management: The Canadian product Viacoram (perindopril/amlodipine) states that concurrent grapefruit juice is not recommended. US labeling for similar amlodipine-containing combination products states that there is no evidence of a significant interaction. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Melatonin: May diminish the antihypertensive effect of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phenytoin: Calcium Channel Blockers may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Calcium Channel Blockers. Management: Avoid use of nimodipine or nifedipine with phenytoin. Monitor for phenytoin toxicity and/or decreased calcium channel blocker effects with any concurrent use. Consider therapy modification

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QuiNIDine: Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of QuiNIDine. QuiNIDine may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some US and Canadian calcium channel blockers contraindicate use with rifampin, however recommendations vary. Consult appropriate labeling. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Simvastatin: AmLODIPine may increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of amlodipine with simvastatin when possible. If used together, avoid doses of simvastatin greater than 20 mg/day (for adults). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Take amlodipine exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take amlodipine with or without food. Take the medicine at the same time each day.

Your blood pressure will need to be checked often.

Your chest pain may become worse when you first start taking amlodipine or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.

If you are being treated for high blood pressure, keep using amlodipine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Your hypertension or heart condition may be treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or stop taking any of your medications without your doctor's advice. This is especially important if you also take nitroglycerin.

Amlodipine is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture, heat, and light.

Usual Adult Dose of Amlodipine for Hypertension:

Initial dose: 5 mg orally once a day
Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-Patients who are small or fragile may be started on 2.5 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Use:
-Alone or in combination with other antihypertensive agents to treat hypertension

Usual Adult Dose of Amlodipine for Angina Pectoris:

Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-In clinical studies, most patients with angina or coronary artery disease (CAD) required 10 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Uses:
-Alone or in combination with other antianginal agents for the symptomatic treatment of chronic stable angina
-Alone or in combination with other antianginal agents for the treatment of confirmed/suspected vasospastic angina
-To reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with recently documented CAD by angiography and without heart failure or an ejection fraction less than 40%

Usual Adult Dose of Amlodipine for Coronary Artery Disease:

Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-In clinical studies, most patients with angina or coronary artery disease (CAD) required 10 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Uses:
-Alone or in combination with other antianginal agents for the symptomatic treatment of chronic stable angina
-Alone or in combination with other antianginal agents for the treatment of confirmed/suspected vasospastic angina
-To reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with recently documented CAD by angiography and without heart failure or an ejection fraction less than 40%

Usual Geriatric Dose of Amlodipine for Hypertension:

Initial dose: 2.5 mg orally once a day
Maintenance dose: 2.5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comment:
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Use:
-Alone or in combination with other antihypertensive agents to treat hypertension

Usual Geriatric Dose of Amlodipine for Angina Pectoris:

Initial dose: 5 mg orally once a day
Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-In clinical studies, most patients with angina or coronary artery disease (CAD) required 10 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Uses:
-Alone or in combination with other antianginal agents for the symptomatic treatment of chronic stable angina
-Alone or in combination with other antianginal agents for the treatment of confirmed/suspected vasospastic angina
-To reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with recently documented CAD by angiography and without heart failure or an ejection fraction less than 40%

Usual Pediatric Dose of Amlodipine for Hypertension:

6 to 17 years:
-Maintenance dose: 2.5 to 5 mg orally once a day
-Maximum dose: 5 mg/day

Comments:
-Doses higher than 5 mg have not been studied in pediatric patients.
The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Use:
-Alone or in combination with other antihypertensive agents to treat hypertension

Applies to amlodipine: oral tablet, oral tablet disintegrating

Along with its needed effects, amlodipine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking amlodipine:

• Swelling of the ankles or feet

• Difficult or labored breathing
• dizziness
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of warmth
• redness of the face, neck, arms, and occasionally, upper chest
• shortness of breath
• tightness in the chest
• wheezing

• Black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• blood in the urine or stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• chills
• cold and clammy skin
• cold sweats
• confusion
• dark yellow urine
• cough
• diarrhea
• dilated neck veins
• dizziness or lightheadedness when getting up from a lying or sitting position
• extra heartbeats
• extreme fatigue
• fainting
• fever
• itching of the skin
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• numbness and tingling of the face, fingers, or toes
• pain in the arms, legs, or lower back, especially pain in the calves or heels upon exertion
• painful or difficult urination
• pale, bluish-colored, or cold hands or feet
• pinpoint red or purple spots on the skin
• red, irritated eyes
• redness of the face, neck, arms, and occasionally, upper chest
• redness, soreness or itching skin
• shakiness in the legs, arms, hands, or feet
• slow or irregular heartbeat
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sores, welting, or blisters
• sudden sweating
• sweating
• swelling of the face, fingers, feet, or lower legs
• swollen glands
• trembling or shaking of the hands or feet
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• weak or absent pulses in the legs
• weakness in the arms, hands, legs, or feet
• weight gain
• yellow eyes or skin

• Abdominal or stomach pain
• clay-colored stools
• diarrhea
• headache
• loss of appetite
• nausea
• rash
• unpleasant breath odor
• vomiting of blood
• yellow eyes or skin

Some side effects of amlodipine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• heartburn
• indigestion
• lack or loss of strength
• muscle cramps
• sleepiness or unusual drowsiness
• stomach discomfort, upset, or pain

• Abnormal dreams
• anxiety
• back pain
• bad unusual or unpleasant (after) taste
• bleeding gums
• blistering, crusting, irritation, itching, or reddening of the skin
• bloating
• bloody nose
• burning feeling in the chest or stomach
• burning while urinating
• burning, dry, or itching eyes
• change in color of the treated skin
• change in sense of smell
• change in taste
• changes in vision
• constipation
• continuing ringing or buzzing or other unexplained noise in the ears
• cracked, dry, or scaly skin
• decreased sexual performance or desire
• depression
• difficulty with moving
• difficulty with swallowing
• discharge, excessive tearing
• double vision
• dry mouth
• dryness of the skin
• excess air or gas in the stomach or intestines
• excessive muscle tone
• eye pain
• feeling of constant movement of self or surroundings
• feeling of unreality
• feeling unusually cold
• flushed, dry skin
• fruit-like breath odor
• full feeling
• general feeling of discomfort or illness
• hair loss or thinning of the hair
• headache, severe and throbbing
• hearing loss
• hyperventilation
• increased appetite
• increased hunger
• increased sweating
• increased thirst
• increased urge to urinate during the night
• increased urination
• irritability
• irritation in the mouth
• lack of feeling or emotion
• loose stools
• loss of memory
• muscle pains or stiffness
• muscle tension or tightness
• muscle weakness
• nervousness
• pain
• pains in the stomach, side, or abdomen, possibly radiating to the back
• passing gas
• problems with memory
• redness and swelling of the gums
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• restlessness
• runny nose
• seeing double
• sensation of spinning
• sense of detachment from self or body
• shakiness and unsteady walk
• shivering
• sleeplessness
• sneezing
• stuffy nose
• sweating
• swollen joints
• tenderness in the stomach area
• thirst
• trouble in holding or releasing urine
• trouble sleeping
• twitching
• unable to sleep
• uncaring
• unexplained weight loss
• unsteadiness, trembling, or other problems with muscle control or coordination
• waking to urinate at night
• weight loss

• Swelling of the breasts or breast soreness in both females and males

Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-In clinical studies, most patients with angina or coronary artery disease (CAD) required 10 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Uses:
-Alone or in combination with other antianginal agents for the symptomatic treatment of chronic stable angina
-Alone or in combination with other antianginal agents for the treatment of confirmed/suspected vasospastic angina
-To reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with recently documented CAD by angiography and without heart failure or an ejection fraction less than 40%

Initial dose: 5 mg orally once a day
Maintenance dose: 5 to 10 mg orally once a day
Maximum dose: 10 mg/day

Comments:
-In clinical studies, most patients with angina or coronary artery disease (CAD) required 10 mg orally once a day.
-The dosage should be adjusted according to patient response. In general, titration should proceed over 7 to 14 days. If clinically warranted, titration may proceed more rapidly, provided the patient is assessed frequently.

Uses:
-Alone or in combination with other antianginal agents for the symptomatic treatment of chronic stable angina
-Alone or in combination with other antianginal agents for the treatment of confirmed/suspected vasospastic angina
-To reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure in patients with recently documented CAD by angiography and without heart failure or an ejection fraction less than 40%

No adjustment recommended.

Summary of Use during Lactation

Limited information indicates that maternal use of amlodipine during breastfeeding has not caused any adverse effects in breastfed infants. However, some mothers appear to excrete rather amounts of amlodipine in milk that might affect some breastfed infants. Breastfed infants of mothers taking amlodipine should be observed carefully for adverse effects. Until more safety data become available, an alternate drug may be preferred.

Drug Levels

Maternal Levels. Thirty-one postpartum women with pregnancy-induced hypertension received amlodipine 5 mg daily by mouth, with the dosage increased as needed to maintain blood pressure of 140/90 mm Hg or less. The final mean dosage for the group was 6 mg (0.01 mg/kg) daily. Simultaneous predose maternal blood and breastmilk samples were obtained within 3 weeks postpartum, after at least 6 days of therapy. The median milk concentration was 11.5 mcg/L (intraquartile range 9.8 to 18 mcg/L). The calculated median infant dosage was 4.2 mcg/kg (intraquartile range 3.1 to 6.3 mcg/kg), which corresponds to a weight-adjusted maternal dosage of 4.2% (intraquartile range 3.1 to 7.3%). In 5 mothers, the weight-adjusted maternal dosage was above 10%, with a maximum value of 15.2% in one mother. The actual infant exposure might be higher than reported in this study because only trough milk values were measured.[1]

Infant Levels. A preterm infant of 32 weeks gestation was breastfed exclusively from day 7 to day 20 postpartum. The infant's mother was taking amlodipine and labetalol in unspecified dosages for hypertension. After 4 days of breastfeeding, the infant's blood amlodipine level was unmeasurable (lower limit of assay not specified).[2]

Eight infants whose mothers were taking amlodipine 5 mg daily during pregnancy were breastfed. Infant serum amlodipine concentrations were unmeasurable (<0.1 mcg/L), although it is unclear from the report whether mothers continued taking amlodipine postpartum.[3]

Effects in Breastfed Infants

A woman took amlodipine for hypertension 5 mg daily beginning 2 weeks postpartum. Her exclusively breastfed infant was examined regularly and at 3 months of age was healthy and had normal physical and neurological development.[4]

One woman received amlodipine 2.5 mg orally twice daily during pregnancy for hypertension associated with glomerulonephritis. The dose was increased to 5 mg twice daily on day 2 postpartum. Her exclusively breastfed infant's growth was normal throughout the first year of life and no adverse effects were noted.[5]

A preterm infant of 32 weeks gestation was breastfed exclusively from day 7 to day 20 postpartum. The infant's mother was taking amlodipine and labetalol in unspecified dosages for hypertension. The infant had apnea episodes unrelated to amlodipine. Growth at 2 months of age was slightly low.[2]

Thirty-one women with pregnancy-induced hypertension postpartum received amlodipine 5 mg daily by mouth, with the dosage increased as needed to maintain blood pressure of 140/90 mm Hg or less. Their breastfed (extent not stated) infants exhibited no observed adverse cardiovascular effects within 3 weeks postpartum, although exact measurement methods were not stated.[1]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Nifedipine, Nitrendipine

References

1. Naito T, Kubono N, Deguchi S et al. Amlodipine passage into breast milk in lactating women with pregnancy-induced hypertension and its estimation of infant risk for breastfeeding. J Hum Lact. 2015;31:301-6. PMID: 25447596

2. Vasa R, Martha Ramirez M. Amlodipine exposure through breastfeeding in a 32 week preterm newborn. Breastfeeding Med. 2013;8 (Suppl 1):S15. Abstract. DOI: doi:10.1089/bfm.2013.9982

3. Morgan JL, Kogutt BK, Meek C et al. Pharmacokinetics of amlodipine besylate during pregnancy-how much infant exposure occurs? Am J Obstet Gynecol. 2017;216:S515-S516.

4. Ahn HK, Nava-Ocampo AA, Han JY et al. Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding. Hypertens Pregnancy. 2007;26:179-87. PMID: 17469008

5. Szucs KA, Axline SE, Rosenman MB. Maternal membranous glomerulonephritis and successful exclusive breastfeeding. Breastfeed Med. 2010;5:123-6. PMID: 20491564

LactMed Record Number

11

Last Revision Date

20170411

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