ADVERSE REACTIONS
In a controlled clinical trial with DynaCirc CR® (isradipine), dose-related edema occurred at an incidence of approximately 9% at 5 mg; 13% at 10 mg; 16% at 15 mg; and 36% at the highest dose studied (20 mg), was mild to moderate in severity, and was not related to age or gender.
The incidences of elicited or volunteered adverse reactions (excluding non-drug related) in the following tables are based on 6-week multicenter, placebo-controlled, double-blind hypertension studies. Less than 1% of DynaCirc CR® (isradipine) or placebo-treated patients discontinued from these studies due to adverse reactions.
The most common adverse experiences (≥1.0%) reported with DynaCirc CR® (isradipine) in a dose-response study are shown in the following table. There were no discontinuations of patients treated with DynaCirc CR® (isradipine) in this study due to these common side effects.
Most Frequently Reported Newly-Occurring Adverse Reactions in Dose-Response Study | DynaCirc CR® (isradipine) | Placebo Group |
| Adverse Reactions (Excluding Non-Drug Related) |
5 mg (N=79)
|
10 mg (N=79)
|
15 mg (N=82)
|
20 mg (N=78)
|
(N=83)
|
| Headache | 13.9% | 12.7% | 18.3% | 10.3% | 15.7% |
| Edema | 8.9% | 12.7% | 15.9% | 35.9% | 3.6% |
| Dizziness | 5.1% | 6.3% | 3.7% | 6.4% | 2.4% |
| Constipation | 3.8% | 1.3% | 1.2% | 2.6% | 0.0% |
| Fatigue | 2.5% | 7.6% | 3.7% | 3.8% | 2.4% |
| Flushing | 2.5% | 3.8% | 1.2% | 1.3% | 1.2% |
| Abdominal Discomfort | 1.3% | 5.1% | 3.7% | 5.1% | 1.2% |
| Rash | 1.3% | 1.3% | 0.0% | 2.6% | 0.0% |
The table below shows elicited or volunteered adverse experiences for DynaCirc CR® (isradipine) treated patients in two 6-week, placebo-controlled, multicenter studies, at doses from 5-20 mg, and considered by the investigator to be at least possibly drug related. The results for DynaCirc CR® (isradipine) treated patients are presented for all doses pooled together (reported by at least 1.0% of active drug treated patients). The incidence of adverse reactions are listed below:
| Adverse Reactions (Excluding Non-Drug Related) | Treatment Group |
|
DynaCirc CR® (isradipine)
(N=422)
| Placebo (N=186) |
| Edema | 15.2% | 2.2% |
| Headache | 13.0% | 12.4% |
| Dizziness | 4.7% | 2.7% |
| Fatigue | 4.3% | 2.2% |
| Abdominal Discomfort | 2.8% | 0.5% |
| Flushing | 1.9% | 0.5% |
| Constipation | 1.7% | 0.0% |
| Palpitations | 1.2% | 0.0% |
| Nausea | 1.2% | 1.6% |
| Abdominal Distention | 1.2% | 0.0% |
The following adverse experiences were reported in 0.5%-1.0% or less of DynaCirc CR® (isradipine) or immediate-release DynaCirc® (isradipine) treated patients in hypertensive studies, or were noted in postmarketing experience with immediate-release DynaCirc® (isradipine) Capsules. More serious events are shown in italics. The relationship of these adverse experiences to isradipine administration is uncertain.
Skin: pruritus, urticaria, angioedema
Musculoskeletal: backache/pain, joint pain, neck pain/sore/stiff, legs ache/pain, cramps of legs/feet
Respiratory: dyspnea, nasal congestion, cough
Cardiovascular: epistaxis, tachycardia, chest pain, shortness of breath, hypotension, syncope, atrial or ventricular fibrillation, myocardial infarction, heart failure
Gastrointestinal: diarrhea, vomiting, appetite increased or decreased
Urogenital: pollakiuria, impotence, dysuria, nocturia
Central Nervous: drowsiness, insomnia, lethargy, nervousness, libido decrease/frigidity, impotence, depression, paresthesia (which includes numbness and tingling), transient ischemic attack, stroke
Autonomic: dry mouth, hyperhidrosis, visual disturbance
Miscellaneous: weight gain, throat discomfort, drug fever, leukopenia, elevated liver function tests
No gastrointestinal bleeding has been reported in clinical trials with DynaCirc CR® (isradipine) Controlled Release Tablets.
In a long-term (one-year) DynaCirc CR® (isradipine) open-label, hypertension trial, the adverse events reported were generally the same as those seen in the short-term placebo-controlled studies. About 6% of DynaCirc CR® (isradipine) treated patients discontinued the long-term trial due to adverse reactions.
With immediate-release DynaCirc® (isradipine) Capsules, most of the adverse experiences were transient, mild, and related to vasodilatory effects. The following table shows the most common adverse events reported in U.S. clinical trials for immediate-release DynaCirc® (isradipine) Capsules, volunteered or elicited, and considered by the investigator to be at least possibly drug related.
| DynaCirc® (isradipine) | Placebo (N=297) % | Active Controls
(N=414) % |
| Adverse Experience | All Doses | 2.5 mg b.i.d. | 5 mg b.i.d.
| 10 mg b.i.d.
|
| 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 |
In open-label, long-term studies of up to two years in duration with immediate-release DynaCirc® (isradipine) Capsules, the adverse experiences 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 in the controlled studies most adverse reactions were mild and transient.
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