FDA label 5e6b3e3e-c1a9-4005-8ea9-2f2640d0cb57

WARNINGS None

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 Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril. (N=414) % Adverse Experience All Doses 2.5 mg b.i.d. 5 mg b.i.d. Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5.0 mg b.i.d. 10 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. 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.

<table width="427.000" ID="id_723fc1a3-40f9-456a-b8be-25e77d1e1ab6"> <caption ID="id_332aabdf-3674-4097-b4e9-6c1ae9ff3425">Most Frequently Reported Newly-Occurring Adverse Reactions in Dose-Response Study</caption> <col width="19.4%"/> <col width="14.1%"/> <col width="16.6%"/> <col width="16.6%"/> <col width="16.6%"/> <col width="16.6%"/> <tbody> <tr ID="id_0d285bf2-a5a5-4899-9e73-69d6c80b2c19"> <td align="left" valign="top" styleCode="Toprule"/> <td align="left" valign="top" colspan="4" styleCode="Toprule"> <content styleCode="bold">DynaCirc CR^&#xAE; (isradipine)</content> </td> <td align="left" valign="top"> <content styleCode="bold">Placebo Group</content> </td> </tr> <tr ID="id_9456c95f-083a-4d8b-adce-8d03d23802af"> <td align="left" valign="top"> <content styleCode="bold">Adverse Reactions (Excluding Non-Drug Related)</content> </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">5 mg (N=79)</content> </paragraph> </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">10 mg (N=79)</content> </paragraph> </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">15 mg (N=82)</content> </paragraph> </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">20 mg (N=78)</content> </paragraph> </td> <td align="left" valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">(N=83)</content> </paragraph> </td> </tr> <tr ID="id_ee7e38cf-d122-40c0-acad-11f2b13e9bdf"> <td align="left" valign="top">Headache</td> <td align="left" valign="top">13.9%</td> <td align="left" valign="top">12.7%</td> <td align="left" valign="top">18.3%</td> <td align="left" valign="top">10.3%</td> <td align="left" valign="top">15.7%</td> </tr> <tr ID="id_2677baa9-3754-476f-9677-80fb69e29c12"> <td align="left" valign="top">Edema</td> <td align="left" valign="top">8.9%</td> <td align="left" valign="top">12.7%</td> <td align="left" valign="top">15.9%</td> <td align="left" valign="top">35.9%</td> <td align="left" valign="top">3.6%</td> </tr> <tr ID="id_b24644cc-8c1e-42b8-a17d-339ecc3af41a"> <td align="left" valign="top">Dizziness</td> <td align="left" valign="top">5.1%</td> <td align="left" valign="top">6.3%</td> <td align="left" valign="top">3.7%</td> <td align="left" valign="top">6.4%</td> <td align="left" valign="top">2.4%</td> </tr> <tr ID="id_99eeb31f-c541-4b38-ac28-85f2a32807c3"> <td align="left" valign="top">Constipation</td> <td align="left" valign="top">3.8%</td> <td align="left" valign="top">1.3%</td> <td align="left" valign="top">1.2%</td> <td align="left" valign="top">2.6%</td> <td align="left" valign="top">0.0%</td> </tr> <tr ID="id_13080a91-d935-4a4f-bcd0-bbc1a93db7f8"> <td align="left" valign="top">Fatigue</td> <td align="left" valign="top">2.5%</td> <td align="left" valign="top">7.6%</td> <td align="left" valign="top">3.7%</td> <td align="left" valign="top">3.8%</td> <td align="left" valign="top">2.4%</td> </tr> <tr ID="id_e423f738-72dc-4f8f-a77c-7781eecc9872"> <td align="left" valign="top">Flushing</td> <td align="left" valign="top">2.5%</td> <td align="left" valign="top">3.8%</td> <td align="left" valign="top">1.2%</td> <td align="left" valign="top">1.3%</td> <td align="left" valign="top">1.2%</td> </tr> <tr ID="id_c7ad22ec-03b1-4b6a-a1fc-c03fcc756cd6"> <td align="left" valign="top">Abdominal Discomfort</td> <td align="left" valign="top">1.3%</td> <td align="left" valign="top">5.1%</td> <td align="left" valign="top">3.7%</td> <td align="left" valign="top">5.1%</td> <td align="left" valign="top">1.2%</td> </tr> <tr ID="id_8ec1ed39-8c02-4098-bb1c-ae0dffe57d20"> <td align="left" valign="top" styleCode="Botrule">Rash</td> <td align="left" valign="top" styleCode="Botrule">1.3%</td> <td align="left" valign="top" styleCode="Botrule">1.3%</td> <td align="left" valign="top" styleCode="Botrule">0.0%</td> <td align="left" valign="top" styleCode="Botrule">2.6%</td> <td align="left" valign="top" styleCode="Botrule">0.0%</td> </tr> </tbody> </table>

<table width="0.000" ID="id_b8474f31-000a-4baf-8260-209e1b3f2eeb"> <col/> <col/> <col/> <tbody> <tr ID="id_cdae0692-571b-4a88-99db-0ccfa1e8a6fb"> <td align="left" valign="top" rowspan="2" styleCode="Toprule"> <content styleCode="bold">Adverse Reactions (Excluding Non-Drug Related)</content> </td> <td align="left" valign="top" colspan="2"> <content styleCode="bold">Treatment Group</content> </td> </tr> <tr ID="id_606c8650-2584-47e3-b73f-5cb8e8e2afe7"> <td align="left" valign="top"> <paragraph> <content styleCode="bold">DynaCirc CR^&#xAE; (isradipine)</content> </paragraph> <paragraph> <content styleCode="bold">(N=422)</content> </paragraph> </td> <td align="left" valign="top"> <content styleCode="bold">Placebo (N=186)</content> </td> </tr> <tr ID="id_7b73ab6e-1a50-411b-9639-063d89f928b8"> <td align="left" valign="top">Edema</td> <td align="left" valign="top">15.2%</td> <td align="left" valign="top">2.2%</td> </tr> <tr ID="id_81aff1d0-df67-4342-9b4a-6a0af692f712"> <td align="left" valign="top">Headache</td> <td align="left" valign="top">13.0%</td> <td align="left" valign="top">12.4%</td> </tr> <tr ID="id_d79c47ad-1c6e-4982-9ba0-38e945251dfe"> <td align="left" valign="top">Dizziness</td> <td align="left" valign="top">4.7%</td> <td align="left" valign="top">2.7%</td> </tr> <tr ID="id_5ddd5902-2b53-4ed9-8c2f-e21f839a2415"> <td align="left" valign="top">Fatigue</td> <td align="left" valign="top">4.3%</td> <td align="left" valign="top">2.2%</td> </tr> <tr ID="id_f0967990-b4c8-4eae-98a8-9ccb8d851c8e"> <td align="left" valign="top">Abdominal Discomfort</td> <td align="left" valign="top">2.8%</td> <td align="left" valign="top">0.5%</td> </tr> <tr ID="id_ea8dd1be-ee28-4922-8cd1-765818f34f60"> <td align="left" valign="top">Flushing</td> <td align="left" valign="top">1.9%</td> <td align="left" valign="top">0.5%</td> </tr> <tr ID="id_8b44ed51-f013-4c1e-b61d-0290b40288c6"> <td align="left" valign="top">Constipation</td> <td align="left" valign="top">1.7%</td> <td align="left" valign="top">0.0%</td> </tr> <tr ID="id_6303d940-d879-4c3b-8a5a-a986c82c8a5a"> <td align="left" valign="top">Palpitations</td> <td align="left" valign="top">1.2%</td> <td align="left" valign="top">0.0%</td> </tr> <tr ID="id_06042e21-95eb-4501-8e70-275fb51e7dc3"> <td align="left" valign="top">Nausea</td> <td align="left" valign="top">1.2%</td> <td align="left" valign="top">1.6%</td> </tr> <tr ID="id_6c58ee0b-5389-4142-97d5-68edd2db9c16"> <td align="left" valign="top" styleCode="Botrule">Abdominal Distention</td> <td align="left" valign="top" styleCode="Botrule">1.2%</td> <td align="left" valign="top" styleCode="Botrule">0.0%</td> </tr> </tbody> </table>

<table width="426.000" ID="id_924ac2fe-0563-4f55-a20a-c6b651e7d51b"> <col width="16.0%"/> <col width="12.4%"/> <col width="14.3%"/> <col width="14.3%"/> <col width="14.3%"/> <col width="14.3%"/> <col width="14.3%"/> <tbody> <tr ID="id_53aebcb0-fcb1-490e-a96b-0add653395a7"> <td align="left" valign="top" styleCode="Toprule"/> <td align="left" valign="top" colspan="4" styleCode="Toprule"> <content styleCode="bold">DynaCirc^&#xAE; (isradipine)</content> </td> <td align="left" valign="top" rowspan="2" styleCode="Toprule"> <content styleCode="bold">Placebo (N=297) %</content> </td> <td align="left" valign="top" rowspan="2"> <content styleCode="bold">Active Controls<footnote ID="id-6691d42a-05c6-4b40-a33f-9351fb01385b">Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril.</footnote> (N=414) %</content> </td> </tr> <tr ID="id_b2270bba-4afe-4a33-b03b-7d6d96db77d5"> <td align="left" valign="top"> <content styleCode="bold">Adverse Experience</content> </td> <td align="left" valign="top"> <content styleCode="bold">All Doses</content> </td> <td align="left" valign="top"> <content styleCode="bold">2.5 mg b.i.d.</content> </td> <td align="left" valign="top"> <content styleCode="bold">5 mg b.i.d.<footnote ID="id-1b5308a0-9d7b-4e4e-9563-a48290bb4673">Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5.0 mg b.i.d.</footnote> </content> </td> <td align="left" valign="top"> <content styleCode="bold">10 mg b.i.d.<footnote ID="id-9fc94b2a-1e07-4c42-a544-edddad27a57d">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.</footnote> </content> </td> </tr> <tr ID="id_b351ea82-1ce9-4bc8-bc6e-5ba2c8489de9"> <td align="left" valign="top">Headache</td> <td align="left" valign="top">13.7</td> <td align="left" valign="top">12.6</td> <td align="left" valign="top">10.7</td> <td align="left" valign="top">22.0</td> <td align="left" valign="top">14.1</td> <td align="left" valign="top">9.4</td> </tr> <tr ID="id_1a92bc35-aaf5-43ac-9376-70e86f7378eb"> <td align="left" valign="top">Dizziness</td> <td align="left" valign="top">7.3</td> <td align="left" valign="top">8.0</td> <td align="left" valign="top">5.3</td> <td align="left" valign="top">3.4</td> <td align="left" valign="top">4.4</td> <td align="left" valign="top">8.2</td> </tr> <tr ID="id_71b0e841-2bf9-4470-8c8c-131e06b4f9c0"> <td align="left" valign="top">Edema</td> <td align="left" valign="top">7.2</td> <td align="left" valign="top">3.5</td> <td align="left" valign="top">8.7</td> <td align="left" valign="top">8.5</td> <td align="left" valign="top">3.0</td> <td align="left" valign="top">2.9</td> </tr> <tr ID="id_503735e9-1457-4000-baf8-f36e99be2341"> <td align="left" valign="top">Palpitations</td> <td align="left" valign="top">4.0</td> <td align="left" valign="top">1.0</td> <td align="left" valign="top">4.7</td> <td align="left" valign="top">5.1</td> <td align="left" valign="top">1.4</td> <td align="left" valign="top">1.5</td> </tr> <tr ID="id_6579d757-e3a6-4c60-8756-285eef7ed44d"> <td align="left" valign="top">Fatigue</td> <td align="left" valign="top">3.9</td> <td align="left" valign="top">2.5</td> <td align="left" valign="top">2.0</td> <td align="left" valign="top">8.5</td> <td align="left" valign="top">0.3</td> <td align="left" valign="top">6.3</td> </tr> <tr ID="id_36b817ce-bb15-4cf7-b177-dcab0eb413b8"> <td align="left" valign="top">Flushing</td> <td align="left" valign="top">2.6</td> <td align="left" valign="top">3.0</td> <td align="left" valign="top">2.0</td> <td align="left" valign="top">5.1</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">1.2</td> </tr> <tr ID="id_4b7f4754-d083-4a11-ae13-b18e0ce4cb56"> <td align="left" valign="top">Chest Pain</td> <td align="left" valign="top">2.4</td> <td align="left" valign="top">2.5</td> <td align="left" valign="top">2.7</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">2.4</td> <td align="left" valign="top">2.9</td> </tr> <tr ID="id_c664519f-fa50-4856-8fb1-fb77c111881c"> <td align="left" valign="top">Nausea</td> <td align="left" valign="top">1.8</td> <td align="left" valign="top">1.0</td> <td align="left" valign="top">2.7</td> <td align="left" valign="top">5.1</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">3.1</td> </tr> <tr ID="id_2d78cc63-f7cd-4715-a225-7fa61f04a263"> <td align="left" valign="top">Dyspnea</td> <td align="left" valign="top">1.8</td> <td align="left" valign="top">0.5</td> <td align="left" valign="top">2.7</td> <td align="left" valign="top">3.4</td> <td align="left" valign="top">1.0</td> <td align="left" valign="top">2.2</td> </tr> <tr ID="id_54204ddc-398e-4242-8318-d85d5a30f37b"> <td align="left" valign="top">Abdominal Discomfort</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">3.3</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">3.9</td> </tr> <tr ID="id_c8d13182-1572-4b47-b294-80ed95cc2a11"> <td align="left" valign="top">Tachycardia</td> <td align="left" valign="top">1.5</td> <td align="left" valign="top">1.0</td> <td align="left" valign="top">1.3</td> <td align="left" valign="top">3.4</td> <td align="left" valign="top">0.3</td> <td align="left" valign="top">0.5</td> </tr> <tr ID="id_c66dedd8-c2f1-4899-8a84-6a269ccdcd00"> <td align="left" valign="top">Rash</td> <td align="left" valign="top">1.5</td> <td align="left" valign="top">1.5</td> <td align="left" valign="top">2.0</td> <td align="left" valign="top">1.7</td> <td align="left" valign="top">0.3</td> <td align="left" valign="top">0.7</td> </tr> <tr ID="id_5fb81f13-3b5e-4d49-963a-fb9c68be4fef"> <td align="left" valign="top">Pollakiuria</td> <td align="left" valign="top">1.5</td> <td align="left" valign="top">2.0</td> <td align="left" valign="top">1.3</td> <td align="left" valign="top">3.4</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">&lt;1.0</td> </tr> <tr ID="id_04942859-8107-4f11-9237-f267f5f1f60e"> <td align="left" valign="top">Weakness</td> <td align="left" valign="top">1.2</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">0.7</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">1.2</td> </tr> <tr ID="id_2661e42c-71c2-4dfb-a7ea-285dc93bf25c"> <td align="left" valign="top">Vomiting</td> <td align="left" valign="top">1.1</td> <td align="left" valign="top">1.0</td> <td align="left" valign="top">1.3</td> <td align="left" valign="top">0.0</td> <td align="left" valign="top">0.3</td> <td align="left" valign="top">0.2</td> </tr> <tr ID="id_19e9e9c6-c69d-4a30-847b-ebcf357e1846"> <td align="left" valign="top" styleCode="Botrule">Diarrhea</td> <td align="left" valign="top" styleCode="Botrule">1.1</td> <td align="left" valign="top" styleCode="Botrule">0.0</td> <td align="left" valign="top" styleCode="Botrule">2.7</td> <td align="left" valign="top" styleCode="Botrule">3.4</td> <td align="left" valign="top" styleCode="Botrule">2.0</td> <td align="left" valign="top" styleCode="Botrule">1.9</td> </tr> </tbody> </table>