FDA label 3d8f2a9d-e940-469a-8bda-5f7a1dc85689

WARNINGS None

ADVERSE REACTIONS 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: In multiple dose U.S. studies in hypertension, 1228 patients received 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 isradipine in U.S. studies of conditions other than hypertension, and 1321 patients received isradipine in non-U.S. studies. About 500 patients received 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 isradipine, including foreign marketing experience. Most adverse reactions were mild and related to the vasodilatory effects of 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 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 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 mg b.i.d. Isradipine Adverse Experience All Doses N=934 % 2.5 mg b.i.d. 199 % 5 mg b.i.d.† 150 % 10 mg b.i.d.†† 59 % Placebo % Active Controls* 414 % Headache Dizziness Edema Palpitations 13.7 7.3 7.2 4.0 12.6 8.0 3.5 1.0 10.7 5.3 8.7 4.7 22.0 3.4 8.5 5.1 14.1 4.4 3.0 1.4 9.4 8.2 2.9 1.5 Fatigue Flushing Chest Pain Nausea 3.9 2.6 2.4 1.8 2.5 3.0 2.5 1.0 2.0 2.0 2.7 2.7 8.5 5.1 1.7 5.1 0.3 0.0 2.4 1.7 6.3 1.2 2.9 3.1 Dyspnea Abdominal Discomfort Tachycardia Rash 1.8 1.7 1.5 1.5 0.5 0.0 1.0 1.5 2.7 3.3 1.3 2.0 3.4 1.7 3.4 1.7 1.0 1.7 0.3 0.3 2.2 3.9 0.5 0.7 Pollakiuria Weakness Vomiting Diarrhea 1.5 1.2 1.1 1.1 2.0 0.0 1.0 0.0 1.3 0.7 1.3 2.7 3.4 0.0 0.0 3.4 0.0 0.0 0.3 2.0 <1.0 1.2 0.2 1.9 †Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †† Initial dose of 2.5 mg b.i.d. followed by sequential titration to 5 mg b.i.d., 7.5 mg b.i.d., and maintenance dose of 10 mg b.i.d. *Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril. Incidence Rates for Isradipine (All Doses) by Week (%) Week N 1 694 2 906 3 649 4 847 5 432 6 494 Adverse Reaction Headache Dizziness Edema Palpitations Fatigue Flushing 6.5 1.6 1.2 1.2 0.4 1.2 6.1 1.9 2.5 1.3 1.0 1.3 5.2 1.7 3.2 1.4 1.4 2.0 5.2 2.2 3.2 1.9 1.2 1.4 5.8 2.3 5.3 2.1 1.2 2.1 4.5 2.0 5.5 1.4 1.6 1.4 Week N 7 153 8 377 9 261 10 362 11 107 12 105 Adverse Reaction Headache Dizziness Edema Palpitations Fatigue Flushing 2.0 2.0 5.9 1.3 2.0 3.3 2.7 1.9 5.0 0.8 2.7 1.3 1.9 2.3 4.6 0.8 1.5 1.1 2.8 3.9 4.7 1.7 1.4 0.8 2.8 4.7 3.8 1.9 0.9 0.0 3.8 3.8 3.8 2.9 1.9 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% of the isradipine-treated patients in hypertensive 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. pruritus, Skin: urticaria cramps of legs/feet Musculoskeletal: cough Respiratory: shortness of breath, hypotension, Cardiovascular: atrial fibrillation, ventricular fibrillation, myocardial infarction, heart failure abdominal discomfort, constipation, diarrhea Gastrointestinal: nocturia Urogenital: drowsiness, insomnia, lethargy, nervousness, impotence, decreased libido, depression, , (which includes numbness and tingling), Nervous System: syncope paresthesia transient ischemic attack, stroke hyperhidrosis, visual disturbance, dry mouth, numbness Autonomic: throat discomfort, Miscellaneous: leukopenia, elevated liver function tests.

<table> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tbody> <tr> <td styleCode=" Toprule "> </td> <td styleCode=" Toprule "> </td> <td align="center" colspan="3" styleCode=" Botrule Toprule "> <content styleCode="bold"> Isradipine</content> </td> <td styleCode=" Toprule "> </td> <td styleCode=" Toprule "> </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule "> <paragraph> <content styleCode="bold">Adverse Experience </content> </paragraph> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">All Doses N=934 % </content> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">2.5 mg b.i.d. 199 % </content> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">5 mg b.i.d.&#x2020; 150 % </content> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">10 mg b.i.d.&#x2020;&#x2020; 59 % </content> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold"> Placebo % </content> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">Active Controls* 414 % </content> </td> </tr> <tr> <td styleCode=" Botrule ">Headache Dizziness Edema Palpitations </td> <td align="center" styleCode=" Botrule ">13.7 7.3 7.2 4.0 </td> <td align="center" styleCode=" Botrule ">12.6 8.0 3.5 1.0 </td> <td align="center" styleCode=" Botrule ">10.7 5.3 8.7 4.7 </td> <td align="center" styleCode=" Botrule ">22.0 3.4 8.5 5.1 </td> <td align="center" styleCode=" Botrule ">14.1 4.4 3.0 1.4 </td> <td align="center" styleCode=" Botrule ">9.4 8.2 2.9 1.5 </td> </tr> <tr> <td styleCode=" Botrule ">Fatigue Flushing Chest Pain Nausea </td> <td align="center" styleCode=" Botrule ">3.9 2.6 2.4 1.8 </td> <td align="center" styleCode=" Botrule ">2.5 3.0 2.5 1.0 </td> <td align="center" styleCode=" Botrule ">2.0 2.0 2.7 2.7 </td> <td align="center" styleCode=" Botrule ">8.5 5.1 1.7 5.1 </td> <td align="center" styleCode=" Botrule ">0.3 0.0 2.4 1.7 </td> <td align="center" styleCode=" Botrule ">6.3 1.2 2.9 3.1 </td> </tr> <tr> <td styleCode=" Botrule ">Dyspnea Abdominal Discomfort Tachycardia Rash </td> <td align="center" valign="bottom" styleCode=" Botrule "> <paragraph>1.8 1.7 1.5 1.5 </paragraph> </td> <td align="center" styleCode=" Botrule ">0.5 0.0 1.0 1.5 </td> <td align="center" styleCode=" Botrule ">2.7 3.3 1.3 2.0 </td> <td align="center" styleCode=" Botrule ">3.4 1.7 3.4 1.7 </td> <td align="center" styleCode=" Botrule ">1.0 1.7 0.3 0.3 </td> <td align="center" styleCode=" Botrule ">2.2 3.9 0.5 0.7 </td> </tr> <tr> <td styleCode=" Botrule ">Pollakiuria Weakness Vomiting Diarrhea </td> <td align="center" styleCode=" Botrule ">1.5 1.2 1.1 1.1 </td> <td align="center" styleCode=" Botrule ">2.0 0.0 1.0 0.0 </td> <td align="center" styleCode=" Botrule ">1.3 0.7 1.3 2.7 </td> <td align="center" styleCode=" Botrule ">3.4 0.0 0.0 3.4 </td> <td align="center" styleCode=" Botrule ">0.0 0.0 0.3 2.0 </td> <td align="center" styleCode=" Botrule ">&lt;1.0 1.2 0.2 1.9 </td> </tr> </tbody> </table>

<table> <col/> <col/> <col/> <col/> <col/> <col/> <col/> <tbody> <tr> <td align="center" valign="bottom" colspan="7" styleCode=" Botrule Toprule "> <content styleCode="bold">Incidence Rates for Isradipine (All Doses) by Week (%) </content> </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule "> <content styleCode="bold">Week N </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">1 694 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">2 906 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">3 649 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">4 847 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">5 432 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">6 494 </content> </td> </tr> <tr> <td valign="bottom" colspan="7" styleCode=" Botrule "> <content styleCode="bold">Adverse Reaction</content> </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule ">Headache Dizziness Edema Palpitations Fatigue Flushing </td> <td align="center" valign="bottom" styleCode=" Botrule ">6.5 1.6 1.2 1.2 0.4 1.2 </td> <td align="center" valign="bottom" styleCode=" Botrule ">6.1 1.9 2.5 1.3 1.0 1.3 </td> <td align="center" valign="bottom" styleCode=" Botrule ">5.2 1.7 3.2 1.4 1.4 2.0 </td> <td align="center" valign="bottom" styleCode=" Botrule ">5.2 2.2 3.2 1.9 1.2 1.4 </td> <td align="center" valign="bottom" styleCode=" Botrule ">5.8 2.3 5.3 2.1 1.2 2.1 </td> <td align="center" valign="bottom" styleCode=" Botrule ">4.5 2.0 5.5 1.4 1.6 1.4 </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule "> <content styleCode="bold">Week N </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold"> 7 153 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">8 377 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">9 261 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">10 362 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">11 107 </content> </td> <td align="center" valign="bottom" styleCode=" Botrule "> <content styleCode="bold">12 105 </content> </td> </tr> <tr> <td valign="bottom" colspan="7" styleCode=" Botrule "> <content styleCode="bold">Adverse Reaction</content> </td> </tr> <tr> <td valign="bottom" styleCode=" Botrule ">Headache Dizziness Edema Palpitations Fatigue Flushing </td> <td align="center" valign="bottom" styleCode=" Botrule ">2.0 2.0 5.9 1.3 2.0 3.3 </td> <td align="center" valign="bottom" styleCode=" Botrule ">2.7 1.9 5.0 0.8 2.7 1.3 </td> <td align="center" valign="bottom" styleCode=" Botrule ">1.9 2.3 4.6 0.8 1.5 1.1 </td> <td align="center" valign="bottom" styleCode=" Botrule ">2.8 3.9 4.7 1.7 1.4 0.8 </td> <td align="center" valign="bottom" styleCode=" Botrule ">2.8 4.7 3.8 1.9 0.9 0.0 </td> <td align="center" valign="bottom" styleCode=" Botrule ">3.8 3.8 3.8 2.9 1.9 0.0 </td> </tr> </tbody> </table>