Amlodipine Besylate: Package Insert and Label Information (Page 3 of 4)

12.4 Pediatric Patients

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m 2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/day. 3 For the rat, the highest dose was, on a mg/m 2 basis, about twice the maximum recommended human dose. 3

Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose 3 of 10 mg/day on a mg/m 2 basis).

3 Based on patient weight of 50 kg

14 CLINICAL STUDIES

14.1 Effects in Hypertension

Adult Patients
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine 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 2.5 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.

14.2 Effects in Chronic Stable Angina

The effectiveness of 5 to 10 mg/day of amlodipine in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1,038 patients (684 amlodipine, 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 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of amlodipine 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).

14.3 Effects in Vasospastic Angina

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

14.4 Effects in Documented Coronary Artery Disease

In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to amlodipine (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 1,318 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 (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 and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, 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 versus Placebo

Figure 1
(click image for full-size original)


Figure 2 – Effects on Primary Endpoint of Amlodipine versus Placebo across Sub-Groups

Figure 2
(click image for full-size original)

Table 1. Incidence of Significant Clinical Outcomes for CAMELOT
Clinical Outcomes N (%) Amlodipine (N=663) Placebo (N=655) Risk Reduction (p-value)
Composite CV Endpoint 110 (16.6) 151 (23.1) 31% (0.003)
Hospitalization for Angina*51 (7.7) 84 (12.8) 42% (0.002)
Coronary Revascularization*78 (11.8) 103 (15.7) 27% (0.033)

*Total patients with these events

14.5 Studies in Patients with Heart Failure

Amlodipine has been compared to placebo in four 8 to12 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 5 to 10 mg in 1,153 patients with NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine 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 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 (n=827) and followed them for a mean of 33 months. There was no statistically significant difference between amlodipine and placebo in the primary endpoint of all-cause mortality (95% confidence limits from 8% reduction to 29% increase on amlodipine). With amlodipine there were more reports of pulmonary edema.

16 HOW SUPPLIED/STORAGE AND HANDLING

2.5 mg Tablets

Amlodipine Besylate Tablets, USP, 2.5 mg (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white,

NDC 43489-102-01 Bottle of 90
NDC 43489-102-10 Bottle of 300

5 mg Tablets

Amlodipine Besylate Tablets, USP, 5 mg (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are supplied as white, octagonal, flat-faced, beveled edged tablets, engraved with “5 mg” on one side and supplied as follows:

NDC 43489-100-01 Bottle of 90
NDC 43489-100-03 Bottle of 500
NDC 43489-100-05 Bottle of 1000

10 mg Tablets

Amlodipine Besylate Tablets, USP, 10 mg (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are supplied as white, round, flat-faced, beveled edged tablets, engraved with “10 mg” on one side and supplied as follows:

NDC 43489-101-01 Bottle of 90
NDC 43489-101-03 Bottle of 500
NDC 43489-101-05 Bottle of 1000

Storage

Store at 20° to 25°C (68° to 77°F) , excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]and dispense in tight, light-resistant containers (USP).

Manufactured by:

China Resources Saike Pharmaceutical Co., Ltd.

No.3, Jinghai 7th street, Tongzhou District, Beijing, 101111, China

Manufactured for:

Secan Pharmaceuticals, Inc.

81 Lancaster Ave. #210, Great Valley Center,

Malvern, PA 19355

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PATIENT INFORMATION LEAFLET Amlodipine Besylate Tablets, USP

Read this information carefully before you start taking amlodipine besylate tablets and each time you refill your prescription. There may be new information. This information does not replace talking with your doctor. If you have any questions about amlodipine , ask your doctor. Your doctor will know if amlodipine is right for you.

What is amlodipine?

Amlodipine is a type of medicine known as a calcium channel blocker (CCB).It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions.

High Blood Pressure (hypertension)

High blood pressure comes from blood pushing too hard against your blood vessels. Amlodipine relaxes your blood vessels, which lets your blood flow more easily and helps lower your blood pressure. Drugs that lower blood pressure lower your risk of having a stroke or heart attack.

Angina

Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Amlodipine can relieve this pain.

Who should not use amlodipine?

Do not use amlodipine if you are allergic to amlodipine (the active ingredient in amlodipine besylate tablets), or to the inactive ingredients. Your doctor or pharmacist can give you a list of these ingredients.

What should I tell my doctor before taking amlodipine?

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:
• ever had heart disease
• ever had liver problems
• are pregnant, or plan to become pregnant. Your doctor will decide if amlodipine is the best treatment for you.
• are breastfeeding. Do not breastfeed while taking amlodipine. You can stop breastfeeding or take a different medicine.

How should I take amlodipine?

• Take amlodipine once a day, with or without food.
• It may be easier to take your dose if you do it at the same time every day, such as with breakfast or dinner, or at bed time. Do not take more than one dose of amlodipine at a time.
• If you miss a dose, take it as soon as you remember. Do not take amlodipine if it has been more than12 hours since you missed your last dose. Wait and take the next dose at your regular time.
Other medicines: You can use nitroglycerin and amlodipine together. If you take nitroglycerin for angina, don’t stop tak ing it while you are taking amlodipine.
• While you are taking amlodipine , do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.
• If you took too much amlodipine , call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.

What should I avoid while taking amlodipine?

Do not start any new prescription or non-prescription medicines or supplements, unless you check with your doctor first.

What are the possible side effects of amlodipine?

Amlodipine may cause the following side effects. Most side effects are mild or moderate:
• swelling of your legs or ankles
• tiredness, extreme sleepiness
• stomach pain, nausea
• dizziness
• flushing (hot or warm feeling in your face)
• arrhythmia (irregular heartbeat)
• heart palpitations (very fast heartbeat)
• muscle rigidity, tremor and/or abnormal muscle movement

It is rare, but when you first start taking amlodipine or increase your dose, you may have a heart attack or your angina may get worse. If that happens, call your doctor right away or go directly to a hospital emergency room.

Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of amlodipine. For a complete list, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Secan Pharmaceuticals, Inc. at 1-610-644-5800 or FDA at 1-800-FDA-1088 or by visiting www.fda.gov/medwatch .

How do I store amlodipine?

Keep amlodipine away from children. Store amlodipine besylate tablets at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep amlodipine out of the light. Do not store in the bathroom. Keep amlodipine in a dry place.

General advice about amlodipine

Sometimes, doctors will prescribe a medicine for a condition that is not written in the patient information leaflets. Only use amlodipine the way your doctor told you to. Do not give amlodipine to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or doctor for information about amlodipine.

Manufactured By :
China Resources Saike Pharmaceutical Co., Ltd.
No. 3, Jinghai 7th Street, Tongzhou District, Beijing, 101111, China

Manufactured for:
Secan Pharmaceuticals, Inc.
81 Lancaster Ave. #210, Great Valley Center,
Malvern, PA 19355

Revised: April 2019

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