Cardizem LA (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 24-month study in rats at oral dosage levels of up to 100 mg/kg/day, and a 21-month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

14 CLINICAL STUDIES

14.1 Hypertension

In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of CARDIZEM LA 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM at roughly 24 hours after the morning (4 AM to 8 AM) or evening (6 PM to 10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) are shown in the table below:

Mean Change in Trough Diastolic Pressure by ABPM

Evening Dosing

Morning Dosing

120 mg

240 mg

360 mg

540 mg

360 mg

-2.0

-4.4

-4.4

-8.1

-6.4

A second randomized, double-blind, parallel-group, dose-response study (N=258) evaluated CARDIZEM LA following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear manner over the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1, and -8.6 mm Hg, respectively.

Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known.

Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.

14.2 Angina

The effects of CARDIZEM LA on angina were evaluated in a randomized, double-blind, parallel-group, dose-response trial of 311 patients with chronic stable angina. Evening doses of 180, 360, and 420 mg were compared to placebo and to 360 mg administered in the morning. All doses of CARDIZEM LA administered at night increased exercise tolerance when compared with placebo after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for all three doses, and no dose-response was demonstrated. CARDIZEM LA, 360 mg, given in the morning, also improved exercise tolerance when measured 25 hours later. As expected, the effect was smaller than the effects measured only 21 hours following nighttime administration. CARDIZEM LA had a larger effect to increase exercise tolerance at peak serum concentrations than at trough.

16 HOW SUPPLIED/STORAGE AND HANDLING

CARDIZEM® LA is supplied as white, capsule-shaped tablets debossed with “B” on one side and the diltiazem content (mg) on the other.

Strength NDC # Bottles of 30 NDC # Bottles of 90

120 mg

0187-2045-30

0187-2045-90

180 mg

0187-2046-30

0187-2046-90

240 mg

0187-2047-30

0187-2047-90

300 mg

0187-2048-30

0187-2048-90

360 mg

0187-2049-30

0187-2049-90

420 mg

0187-2050-30

0187-2050-90

Storage conditions: Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86°F) [see USP Controlled Room Temperature].

Avoid excessive humidity and temperatures above 30°C (86°F).

Dispense in tight, light resistant container as defined in USP.

17 PATIENT COUNSELING INFORMATION

Advise patients:

That the CARDIZEM LA tablet should be swallowed whole and not chewed or crushed.
To consult the physician who prescribed CARDIZEM LA before taking or stopping any other medications, including over-the-counter products or nutritional supplements, such as St. John’s wort.
To contact the physician who prescribed CARDIZEM LA or any other physician immediately if they experience possible adverse reactions, including bradycardia, arrhythmias, symptoms indicative of hypotension or heart failure, hepatic and skin reactions.
To consult their physician if they become pregnant while taking CARDIZEM LA or plan to become pregnant.

Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

By:
Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7 Canada

Cardizem is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates.

© Valeant Pharmaceuticals North America LLC

9457001

20001733

Rev. 11/2016

Principal Display Panel – 120 mg Bottle Label

NDC 0187-2045-90

Rx only

CARDIZEM® LA
(Diltiazem Hydrochloride)Extended-Release Tablets

120 mg

90 Tablets

VALEANT

Cardizem120mg-90-tabs.jpg
(click image for full-size original)

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