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In multiple dose U.S. studies in hypertension, 1228 patients received DynaCirc® (isradipine) alone or in combination with other agents, principally a thiazide diuretic, 934 of them in controlled comparisons with placebo or active agents. An additional 652 patients (which includes 374 normal volunteers) received DynaCirc® (isradipine) in U.S. studies of conditions other than hypertension, and 1321 patients received DynaCirc® (isradipine) in non-U.S. studies. About 500 patients received DynaCirc® (isradipine) in long-term hypertension studies, 410 of them for at least 6 months. The adverse reaction rates given below are principally based on controlled hypertension studies, but rarer serious events are derived from all exposures to DynaCirc® (isradipine), including foreign marketing experience.

Most adverse reactions were mild and related to the vasodilatory effects of DynaCirc (isradipine) ® (dizziness, edema, palpitations, flushing, tachycardia), and many were transient. About 5% of isradipine patients left studies prematurely because of adverse reactions (vs. 3% of placebo patients and 6% of active control patients), principally due to headache, edema, dizziness, palpitations, and gastrointestinal disturbances.

The following table shows the most common adverse reactions, volunteered or elicited, considered by the investigator to be at least possibly drug related. The results for the DynaCirc® (isradipine) treated patients are presented for all doses pooled together (reported by 1% or greater of patients receiving any dose of isradipine), and also for the two treatment regimens most applicable to the treatment of hypertension with DynaCirc® (isradipine): (1) initial and maintenance dose of 2.5 mg b.i.d., and (2) initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5.0 mg b.i.d.

DynaCirc® (isradipine)

N= All Doses 934 2.5 mg b.i.d. 199 5 mg b.i.d.* 150 10 mg b.i.d. 59 Placebo 297 Active Controls 414
Adverse Experience % % % % % %
Headache 13.7 12.6 10.7 22.0 14.1 9.4
Dizziness 7.3 8.0 5.3 3.4 4.4 8.2
Edema 7.2 3.5 8.7 8.5 3.0 2.9
Palpitations 4.0 1.0 4.7 5.1 1.4 1.5
Fatigue 3.9 2.5 2.0 8.5 0.3 6.3
Flushing 2.6 3.0 2.0 5.1 0.0 1.2
Chest Pain 2.4 2.5 2.7 1.7 2.4 2.9
Nausea 1.8 1.0 2.7 5.1 1.7 3.1
Dyspnea 1.8 0.5 2.7 3.4 1.0 2.2
Abdominal Discomfort 1.7 0.0 3.3 1.7 1.7 3.9
Tachycardia 1.5 1.0 1.3 3.4 0.3 0.5
Rash 1.5 1.5 2.0 1.7 0.3 0.7
Pollakiuria 1.5 2.0 1.3 3.4 0.0 < 1.0
Weakness 1.2 0.0 0.7 0.0 0.0 1.2
Vomiting 1.1 1.0 1.3 0.0 0.3 0.2
Diarrhea 1.1 0.0 2.7 3.4 2.0 1.9
* Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5.0 mg b.i.d.
Initial dose of 2.5 mg b.i.d. followed by sequential titration to 5.0 mg b.i.d., 7.5 mg b.i.d., and maintenance dose of 10.0 mg b.i.d.
Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril.

Except for headache, which is not clearly drug-related (see previous table), the more frequent adverse reactions listed show little change, or increase slightly, in frequency over time, as shown in the following table:

Incidence Rates for DynaCirc (isradipine) (All Doses) by Week (%)

Week 1 2 3 4 5 6
N 94 906 649 847 432 494
Adverse Reaction            
Headache 6.5 6.1 5.2 5.2 5.8 4.5
Dizziness 1.6 1.9 1.7 2.2 2.3 2.0
Edema 1.2 2.5 3.2 3.2 5.3 5.5
Palpitations 1.2 1.3 1.4 1.9 2.1 1.4
Fatigue 0.4 1.0 1.4 1.2 1.2 1.6
Flushing 1.2 1.3 2.0 1.4 2.1 1.4
Week 7 8 9 10 11 12
N 153 377 261 362 107 105
Adverse Reaction            
Headache 2.0 2.7 1.9 2.8 2.8 3.8
Dizziness 2.0 1.9 2.3 3.9 4.7 3.8
Edema 5.9 5.0 4.6 4.7 3.8 3.8
Palpitations 1.3 0.8 0.8 1.7 1.9 2.9
Fatigue 2.0 2.7 1.5 1.4 0.9 1.9
Flushing 3.3 1.3 1.1 0.8 0.0 0.0

Edema, palpitations, fatigue, and flushing appear to be dose-related, especially at the higher doses of 15-20 mg/day. In open-label, long-term studies of up to two years in duration, the adverse events reported were generally the same as those reported in the short-term controlled trials. The overall frequencies of these adverse events were slightly higher in the long-term than in the controlled studies, but as in the controlled trials most adverse reactions were mild and transient.

The following adverse experiences were reported in 0.5%-1.0% of the isradipine-treated patients in hypertension studies, or are rare. More serious events from this and other data sources, including postmarketing exposure, are shown in italics. The relationship of these adverse events to isradipine administration is uncertain.

Skin: pruritus, urticaria

Musculoskeletal: cramps of legs/feet

Respiratory: cough

Cardiovascular: shortness of breath, hypotension, atrial fibrillation, ventricular fibrillation, myocardial infarction, heart failure

Gastrointestinal: abdominal discomfort, constipation, diarrhea

Urogenital: nocturia

Nervous System: drowsiness, insomnia, lethargy, nervousness, impotence, decreased libido, depression, syncope, paresthesia (which includes numbness and tingling), transient ischemicattack, stroke

Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness

Miscellaneous: throat discomfort, leukopenia, elevated liver function tests