FDA label e87e2c26-cd7c-ee2a-e053-2995a90aaef9

WARNINGS None

ADVERSE REACTIONS 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 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: † 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%-1.0% 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 ischemic attack, stroke Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness Miscellaneous: throat discomfort, leukopenia, elevated liver function tests To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%"><tbody><tr><td styleCode="Toprule "/><td styleCode="Toprule "/><td align="center" colspan="3" styleCode="Botrule Toprule "><content styleCode="bold">Isradipine</content></td><td styleCode="Toprule "/><td styleCode="Toprule "/></tr><tr><td styleCode="Botrule " valign="bottom"><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" styleCode="Botrule ">1.8 1.7 1.5 1.5 <paragraph/></td><td align="center" styleCode="Botrule ">0.5 0.0 1.0 1.5 <paragraph/></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 width="100%"><tbody><tr><td align="center" colspan="7" styleCode="Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Incidence Rates for Isradipine</content></paragraph><paragraph><content styleCode="bold">(All Doses) by Week (%) </content></paragraph></td></tr><tr><td styleCode="Botrule " valign="bottom"><content styleCode="bold">Week N </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">1 694 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">2 906 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">3 649 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">4 847 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">5 432 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">6 494 </content></td></tr><tr><td colspan="7" styleCode="Botrule " valign="bottom"><content styleCode="bold">Adverse Reaction</content></td></tr><tr><td styleCode="Botrule " valign="bottom">Headache Dizziness Edema Palpitations Fatigue Flushing </td><td align="center" styleCode="Botrule " valign="bottom">6.5 1.6 1.2 1.2 0.4 1.2 </td><td align="center" styleCode="Botrule " valign="bottom">6.1 1.9 2.5 1.3 1.0 1.3 </td><td align="center" styleCode="Botrule " valign="bottom">5.2 1.7 3.2 1.4 1.4 2.0 </td><td align="center" styleCode="Botrule " valign="bottom">5.2 2.2 3.2 1.9 1.2 1.4 </td><td align="center" styleCode="Botrule " valign="bottom">5.8 2.3 5.3 2.1 1.2 2.1 </td><td align="center" styleCode="Botrule " valign="bottom">4.5 2.0 5.5 1.4 1.6 1.4 </td></tr><tr><td styleCode="Botrule " valign="bottom"><content styleCode="bold">Week N </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">7 153 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">8 377 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">9 261 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">10 362 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">11 107 </content></td><td align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">12 105 </content></td></tr><tr><td colspan="7" styleCode="Botrule " valign="bottom"><content styleCode="bold">Adverse Reaction</content></td></tr><tr><td styleCode="Botrule " valign="bottom">Headache Dizziness Edema Palpitations Fatigue Flushing </td><td align="center" styleCode="Botrule " valign="bottom">2.0 2.0 5.9 1.3 2.0 3.3 </td><td align="center" styleCode="Botrule " valign="bottom">2.7 1.9 5.0 0.8 2.7 1.3 </td><td align="center" styleCode="Botrule " valign="bottom">1.9 2.3 4.6 0.8 1.5 1.1 </td><td align="center" styleCode="Botrule " valign="bottom">2.8 3.9 4.7 1.7 1.4 0.8 </td><td align="center" styleCode="Botrule " valign="bottom">2.8 4.7 3.8 1.9 0.9 0.0 </td><td align="center" styleCode="Botrule " valign="bottom">3.8 3.8 3.8 2.9 1.9 0.0 </td></tr></tbody></table>