HEMANGEOL oral solution contains the beta-adrenergic blocker propranolol hydrochloride and is indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy.

{ "type": "p", "children": [], "text": "HEMANGEOL oral solution contains the beta-adrenergic blocker propranolol hydrochloride and is indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy." }

Initiate treatment at ages 5 weeks to 5 months.

{ "type": "p", "children": [], "text": "Initiate treatment at ages 5 weeks to 5 months." }

The recommended starting dose of HEMANGEOL is 0.15 mL/kg (0.6 mg/kg) (see Table 1) twice daily, taken at least 9 hours apart. After 1 week, increase the daily dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks of treatment, increase the dose to 0.4 mL/kg (1.7 mg/kg) twice daily and maintain this for 6 months. Readjust the dose periodically as the child’s weight increases.

{ "type": "p", "children": [], "text": "The recommended starting dose of HEMANGEOL is 0.15 mL/kg (0.6 mg/kg) (see Table 1) twice daily, taken at least 9 hours apart. After 1 week, increase the daily dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks of treatment, increase the dose to 0.4 mL/kg (1.7 mg/kg) twice daily and maintain this for 6 months. Readjust the dose periodically as the child’s weight increases." }

To reduce the risk of hypoglycemia, administer HEMANGEOL orally during or right after a feeding. Skip the dose if the child is not eating or is vomiting [see  Warnings and Precautions (5.1)] .

{ "type": "p", "children": [], "text": "To reduce the risk of hypoglycemia, administer HEMANGEOL orally during or right after a feeding. Skip the dose if the child is not eating or is vomiting \n \n \n [see \n \n \n Warnings and Precautions (5.1)]\n \n \n . \n \n\n " }

Monitor heart rate and blood pressure for 2 hours after HEMANGEOL initiation or dose increases [see  Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Monitor heart rate and blood pressure for 2 hours after HEMANGEOL initiation or dose increases \n \n \n [see \n \n \n Warnings and Precautions (5.2)].\n \n \n \n" }

If hemangiomas recur, treatment may be re-initiated [see Clinical Studies (14)] .

{ "type": "p", "children": [], "text": "If hemangiomas recur, treatment may be re-initiated \n \n \n [see Clinical Studies (14)]\n \n \n .\n \n\n " }

HEMANGEOL is supplied with an oral dosing syringe for administration. Administration directly into the child’s mouth is recommended. Nevertheless, if necessary, the product may be diluted in a small quantity of milk or fruit juice, given in a baby’s bottle.

{ "type": "p", "children": [], "text": "HEMANGEOL is supplied with an oral dosing syringe for administration. Administration directly into the child’s mouth is recommended. Nevertheless, if necessary, the product may be diluted in a small quantity of milk or fruit juice, given in a baby’s bottle." }

Table 1. Dose Titration According to Weight

{ "type": "p", "children": [], "text": "\nTable 1. Dose Titration According to Weight\n" }

<div class="scrollingtable"><table> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule" valign="bottom"> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">  <span class="Bold">Week 1</span></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Week 2</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Week 3 (maintenance)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> <p class="First"> <span class="Bold">Weight (kg)</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Volume administered </span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Volume administered</span> </p> </td><td align="center" class="Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Volume administered</span> </p> </td> </tr> <tr> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">twice a day</span>  </td><td align="center" class="Lrule Rrule" valign="top"><span class="Bold">twice a day</span>  </td><td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">twice a day</span>  </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 to &lt;2.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.3 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.6 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.8 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.5 to &lt;3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.8 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 to &lt;3.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.5 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.9 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.2 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.5 to &lt;4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.5 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.4 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 to &lt;4.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.6 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.2 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5 to &lt;5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.7 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.4 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.8 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 to &lt;5.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.8 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.5 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.5 to &lt;6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.8 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.7 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.2 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 to &lt;6.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.9 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.8 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.4 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.5 to &lt;7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 to &lt;7.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.8 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7.5 to &lt;8</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.1 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.3 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 to &lt;8.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.2 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.4 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.2 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.5 to &lt;9</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.3 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.6 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.4 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9 to &lt;9.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.4 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.7 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.6 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9.5 to &lt;10</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.4 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.9 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.8 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 to &lt;10.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.5 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10.5 to &lt;11</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.6 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.2 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.2 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 to &lt;11.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.7 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.3 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.4 mL</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11.5 to &lt;12</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.7 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.5 mL</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.6 mL</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top">12 to &lt;12.5</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">1.8 mL</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">3.6 mL</td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top">4.8 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col/>\n<col/>\n<col/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule\" valign=\"bottom\"> </td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"> \n \n \n <span class=\"Bold\">Week 1</span></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Week 2</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Week 3 (maintenance)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" rowspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Weight (kg)</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Volume administered </span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Volume administered</span>\n</p>\n</td><td align=\"center\" class=\"Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Volume administered</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Lrule Rrule\" valign=\"top\"><span class=\"Bold\">twice a day</span> \n \n \n </td><td align=\"center\" class=\"Lrule Rrule\" valign=\"top\"><span class=\"Bold\">twice a day</span> \n \n \n </td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Bold\">twice a day</span> \n \n \n </td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2 to &lt;2.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.3 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.6 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.8 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.5 to &lt;3</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.4 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.8 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3 to &lt;3.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.5 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.9 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.2 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.5 to &lt;4</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.5 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.1 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.4 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4 to &lt;4.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.6 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.2 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.6 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4.5 to &lt;5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.7 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.4 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.8 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">5 to &lt;5.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.8 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.5 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">5.5 to &lt;6</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.8 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.7 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.2 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">6 to &lt;6.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">0.9 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.8 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.4 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">6.5 to &lt;7</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.6 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">7 to &lt;7.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.1 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.1 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.8 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">7.5 to &lt;8</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.1 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.3 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">8 to &lt;8.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.2 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.4 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.2 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">8.5 to &lt;9</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.3 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.6 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.4 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">9 to &lt;9.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.4 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.7 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.6 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">9.5 to &lt;10</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.4 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">2.9 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.8 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">10 to &lt;10.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.5 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">10.5 to &lt;11</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.6 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.2 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4.2 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">11 to &lt;11.5</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.7 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.3 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4.4 mL</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">11.5 to &lt;12</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">1.7 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">3.5 mL</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4.6 mL</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">12 to &lt;12.5</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">1.8 mL</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">3.6 mL</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">4.8 mL</td>\n</tr>\n</tbody>\n</table></div>" }

Oral solution: 4.28 mg/mL propranolol hydrochloride.

{ "type": "p", "children": [], "text": "Oral solution: 4.28 mg/mL propranolol hydrochloride." }

Alcohol-, paraben- and sugar-free.

{ "type": "p", "children": [], "text": "Alcohol-, paraben- and sugar-free." }

HEMANGEOL is contraindicated in the following conditions:

{ "type": "p", "children": [], "text": "HEMANGEOL is contraindicated in the following conditions:" }

{ "type": "ul", "children": [ "Premature infants with corrected age < 5 weeks", "Infants weighing less than 2 kg", "Known hypersensitivity to propranolol or any of the excipients \n \n \n [see \n \n \n Description (11)]\n \n \n \n", "Asthma or history of bronchospasm", "Heart rate <80 beats per minute, greater than first degree heart block, or decompensated heart failure", "Blood pressure <50/30 mmHg", "Pheochromocytoma" ], "text": "" }

HEMANGEOL prevents the response of endogenous catecholamines to correct hypoglycemia and masks the adrenergic warning signs of hypoglycemia, particularly tachycardia, palpitations and sweating. HEMANGEOL can cause hypoglycemia at any time during treatment. Risk is increased during a fasting period (e.g., poor oral food intake, infection, vomiting) or when glucose demands are increased (e.g., cold, stress, infections). Withhold the dose under these conditions. Hypoglycemia may present in the form of seizures, lethargy, or coma. Discontinue HEMANGEOL if hypoglycemia develops and treat appropriately Concomitant treatment with corticosteroids may increase the risk of hypoglycemia [ see Drug Interactions (7) ] .

HEMANGEOL may cause or worsen bradycardia or hypotension. In the studies of HEMANGEOL for infantile hemangioma the mean decrease in heart rate was about 7 bpm with little effect on blood pressure. Monitor heart rate and blood pressure after treatment initiation or increase in dose. Discontinue treatment if severe (<80 beats per minute) or symptomatic bradycardia or hypotension (systolic blood pressure <50 mmHg) occurs.

HEMANGEOL can cause bronchospasm; do not use in patients with asthma or a history of bronchospasm. Interrupt treatment in the event of a lower respiratory tract infection associated with dyspnea and wheezing.

Sympathetic stimulation supports circulatory function in patients with congestive heart failure, beta blockade may precipitate more severe failure.

By dropping blood pressure, HEMANGEOL may increase the risk of stroke in PHACE syndrome patients with severe cerebrovascular anomalies. Investigate infants with large facial infantile hemangioma for potential arteriopathy associated with PHACE syndrome prior to HEMANGEOL therapy.

Beta-blockers will interfere with epinephrine used to treat serious anaphylaxis.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in clinical practice.

Clinical Trials Experience with HEMANGEOL in Infants with proliferating infantile hemangioma In clinical trials for proliferating infantile hemangioma, the most frequently reported adverse reactions (>10%) in infants treated with HEMANGEOL were sleep disorders, aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever, diarrhea, and vomiting. Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

Overall, 479 patients in the pooled safety population were exposed to study drug in the clinical study program (456 in placebo-controlled trials). A total of 424 patients were treated with HEMANGEOL at doses 1.2 mg/kg/day or 3.4 mg/kg/day for 3 or 6 months. Of these, 63% of patients were aged 91-150 days and 37% were aged 35-90 days at randomization.

The following table lists according to the dosage the most common adverse reactions (treatment-emergent adverse events with an incidence at least 3% greater on one of the two doses than on placebo).

Table 2. Treatment-emergent adverse events occurring at least 3% more often on HEMANGEOL than on placebo

<div class="scrollingtable"><table> <colgroup> <col/> <col/> <col/> <col/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Reaction</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo <br/> <br/> N=236 </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">HEMANGEOL <br/> <br/> 1.2 mg/kg/day <br/> <br/> N=200 </span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">HEMANGEOL <br/> <br/> 3.4 mg/kg/day <br/> <br/> N=224 </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Sleep disorder</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.9%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">17.5%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16.1%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Bronchitis</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13.4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Peripheral coldness</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.7</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Agitation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.1</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nightmare</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.7</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Irritability</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.3</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1.3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased appetite</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.6</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Abdominal pain</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3.5</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0.4</p> </td> </tr> </tbody> </table></div>

The following adverse events have been observed during clinical studies, with an incidence of less than 1%:

Cardiac disorders: Second degree atrioventricular heart block, in a patient with underlying conduction disorder, required definitive treatment discontinuation [see Warnings and Precautions(5.4)] .

Skin and subcutaneous tissue disorders: Urticaria, alopecia

Investigations: Decreased blood glucose, decreased heart rate

Compassionate Use Program

More than 600 infants received HEMANGEOL in a compassionate use program (CUP). Mean age at treatment initiation was 3.6 months. Mean dose of HEMANGEOL was 2.2 mg/kg/day and mean treatment duration was 7.1 months.

The adverse reactions reported in the CUP were similar to the ADRs observed during clinical trials but some were more severe.

The following adverse reactions have been identified during post-approval use of propranolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are as follows:

Blood and lymphatic system disorders:Agranulocytosis

Psychiatric disorders: Hallucination

Skin and subcutaneous tissues disorders: Purpura, dermatitis psoriasform

In the absence of specific studies in children, the drug interactions with propranolol are those known in adults. Consider both the infant’s medications and those of a nursing mother.

{ "type": "p", "children": [], "text": "In the absence of specific studies in children, the drug interactions with propranolol are those known in adults. Consider both the infant’s medications and those of a nursing mother." }

Pharmacokinetic drug interactions

{ "type": "p", "children": [], "text": "\nPharmacokinetic drug interactions\n" }

Impact of co-administered drugs on propranolol: CYP2D6, CYP1A2 or CYP2C19 inhibitors increase propranolol plasma concentration. CYP1A2 inducers (phenytoin, phenobarbital) or CYP2C19 inducers (rifampin) decrease propranolol plasma concentration when co-administered.

{ "type": "p", "children": [], "text": "\nImpact of co-administered drugs on propranolol: CYP2D6, CYP1A2 or CYP2C19 inhibitors increase propranolol plasma concentration. CYP1A2 inducers (phenytoin, phenobarbital) or CYP2C19 inducers (rifampin) decrease propranolol plasma concentration when co-administered.\n " }

Pharmacodynamic drug interactions

{ "type": "p", "children": [], "text": "\nPharmacodynamic drug interactions\n" }

Corticosteroids: Patients on corticosteroids may be at increased risk of hypoglycemia because of loss of the counter-regulatory cortisol response; monitor patients for signs of hypoglycemia.

{ "type": "p", "children": [], "text": "\nCorticosteroids: Patients on corticosteroids may be at increased risk of hypoglycemia because of loss of the counter-regulatory cortisol response; monitor patients for signs of hypoglycemia.\n " }

Of 460 infants with proliferating infantile hemangioma requiring systemic therapy who were treated with HEMANGEOL starting at 5 weeks to 5 months of age, 60% had complete or nearly complete resolution of their hemangioma at Week 24 [see  Clinical Studies (14)].

Safety and effectiveness for infantile hemangioma have not been established in pediatric patients greater than 1 year of age.

There is no experience in infants with hepatic impairment .

There is no experience in infants with renal impairment .

Few cases of propranolol overdose were reported. For a single intake, the maximum dose was 20 mg/kg. Symptomatic cases featured hypotension, hypoglycemic seizure, and restlessness/euphory/insomnia; for most cases, propranolol was maintained or reintroduced.

{ "type": "p", "children": [], "text": "Few cases of propranolol overdose were reported. For a single intake, the maximum dose was 20 mg/kg. Symptomatic cases featured hypotension, hypoglycemic seizure, and restlessness/euphory/insomnia; for most cases, propranolol was maintained or reintroduced." }

The toxicity of beta-blockers is an extension of their therapeutic effects:

{ "type": "p", "children": [], "text": "The toxicity of beta-blockers is an extension of their therapeutic effects:" }

- Cardiac symptoms of mild to moderate poisoning are decreased heart rate and hypotension. Atrioventricular blocks, intraventricular conduction delays, and congestive heart failure can occur with more severe poisoning.

{ "type": "p", "children": [], "text": "- Cardiac symptoms of mild to moderate poisoning are decreased heart rate and hypotension. Atrioventricular blocks, intraventricular conduction delays, and congestive heart failure can occur with more severe poisoning. " }

- Bronchospasm may develop particularly in patients with asthma.

{ "type": "p", "children": [], "text": "- Bronchospasm may develop particularly in patients with asthma." }

- Hypoglycemia may develop and manifestations of hypoglycemia (tremor, tachycardia) may be masked by other clinical effects of beta-blocker toxicity.

{ "type": "p", "children": [], "text": "- Hypoglycemia may develop and manifestations of hypoglycemia (tremor, tachycardia) may be masked by other clinical effects of beta-blocker toxicity." }

Support and treatment: Place the patient on a cardiac monitor, and monitor vital signs, mental status and blood glucose. Give intravenous fluids for hypotension and atropine for bradycardia. Glucagon then catecholamines should be considered if the patient does not respond appropriately to IV fluid. Isoproterenol and aminophylline may be used for bronchospasm. 

{ "type": "p", "children": [], "text": "\nSupport and treatment: Place the patient on a cardiac monitor, and monitor vital signs, mental status and blood glucose. Give intravenous fluids for hypotension and atropine for bradycardia. Glucagon then catecholamines should be considered if the patient does not respond appropriately to IV fluid. Isoproterenol and aminophylline may be used for bronchospasm.  \n \n\n " }

Propranolol is not dialyzable.

{ "type": "p", "children": [], "text": "Propranolol is not dialyzable." }

HEMANGEOL is an oral solution of propranolol that is alcohol free, paraben free and sugar free. Each mL of HEMANGEOL contains 4.28 mg of propranolol hydrochloride, USP equivalent to 3.75 mg of propranolol.

{ "type": "p", "children": [], "text": "HEMANGEOL is an oral solution of propranolol that is alcohol free, paraben free and sugar free. Each mL of HEMANGEOL contains 4.28 mg of propranolol hydrochloride, USP equivalent to 3.75 mg of propranolol." }

Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (2RS)1-[(1-methylethyl)amino]-3-(naphthalene-1-yloxy)-propan-2-ol hydrochloride. Its structural formula is shown in Figure 1:

{ "type": "p", "children": [], "text": "Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (2RS)1-[(1-methylethyl)amino]-3-(naphthalene-1-yloxy)-propan-2-ol hydrochloride. Its structural formula is shown in Figure 1:" }

Figure 1. Propranolol HCl Structure

{ "type": "p", "children": [], "text": "\nFigure 1. Propranolol HCl Structure\n" }

Molecular formula: C 16H 21NO 2-HCl

{ "type": "p", "children": [], "text": "Molecular formula: C\n \n \n 16H\n \n \n 21NO\n \n \n 2-HCl\n \n\n " }

Propranolol hydrochloride is a stable, white, crystalline solid with a molecular weight of 295.8. It is readily soluble in water and ethanol.

{ "type": "p", "children": [], "text": "Propranolol hydrochloride is a stable, white, crystalline solid with a molecular weight of 295.8. It is readily soluble in water and ethanol." }

HEMANGEOL contains the following inactive ingredients: strawberry/vanilla flavorings, hydroxyethylcellulose, saccharin sodium, citric acid monohydrate, and water.

{ "type": "p", "children": [], "text": "HEMANGEOL contains the following inactive ingredients: strawberry/vanilla flavorings, hydroxyethylcellulose, saccharin sodium, citric acid monohydrate, and water." }

The mechanism of HEMANGEOL’s effects on infantile hemangiomas is not well understood.

Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.

Propranolol selectively blocks beta-adrenergic receptors, leaving alpha-adrenergic responses intact. There are two well-characterized subtypes of beta receptors (beta1 and beta2); propranolol interacts with both subtypes equally.

Beta1-adrenergic receptors are found primarily in the heart. Blockade of cardiac beta1-adrenergic receptors leads to a decrease in the activity of both normal and ectopic pacemaker cells and a decrease in A-V nodal conduction velocity. Blockade of cardiac beta1-adrenergic receptors also decreases the myocardial force of contraction and may provoke cardiac decompensation in patients with minimal cardiac reserve.

Beta2-adrenergic receptors are found predominantly in smooth muscle-vascular, bronchial, gastrointestinal and genitourinary. Blockade of these receptors results in constriction. Propranolol’s beta-blocking effects are attributable to its S(-) enantiomer.

Pharmacodynamic drug interactions

Alpha blockers: Co-administration of beta-blockers with alpha blockers (prazosin) has been associated with prolongation of first dose hypotension and syncope.

Antidepressants: The hypotensive effect of MAO inhibitors and tricyclic antidepressants is exacerbated when administered with beta-blockers.

Nonsteroidal anti-inflammatory drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-adrenoreceptor blocking agents. Monitor blood pressure.

Adults

Absorption: Propranolol is almost completely absorbed after oral administration. However, it undergoes an extensive first-pass metabolism by the liver and on average; only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose. Administration of protein-rich foods increases the bioavailability of propranolol by about 50% with no change in time to peak concentration.

Propranolol is a substrate for the intestinal efflux transporter, P-glycoprotein (P-gp). However, studies suggest that P-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.

Distribution: Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The volume of distribution of propranolol is approximately 4 L/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.

Propranolol is extensively metabolized with most metabolites appearing in the urine.

Metabolism: Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. The percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major final metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies indicated that CYP2D6 (aromatic hydroxylation), CYP1A2 (chain oxidation) and to a less extent CYP2C19 were involved in propranolol metabolism.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life.

Elimination:The plasma half-life of propranolol ranges from 3 to 6 hours. Less than 1% of a dose is excreted as unchanged drug in the urine.

Infants

The pharmacokinetics of propranolol and 4-OH-propranolol were evaluated in a multiple dose 12 week study conducted in 23 male and female infants 35 to 150 days of age with hemangioma. The infants were stratified by age (35 to 90 days and 91 to 150 days). The starting dose was 1.2 mg/kg/day which was titrated to the target dose of 3.4 mg/kg/day in 1.1 mg/kg/day increments at weekly intervals. At steady state, following administration of 3.4 mg/kg/day twice daily, peak plasma propranolol concentrations were observed within 2 hours of oral administration. Clearance of propranolol in infants was similar across the age range studied (2.7 (SD=0.03) L/h/kg in infants <90 days of age and 3.3 (SD=0.35) L/h/kg in infants >90 days of age) and to that in adults when adjusted by body weight. The median elimination half-life of propranolol was about 3.5 hours. Plasma propranolol concentrations approximate a dose proportional increase in the dose range of 1.2 mg/kg/day to 3.4 mg/kg/day.

Plasma concentration of 4-OH-propranolol, the main metabolite, was about 5% of total plasma exposure of propranolol.

Sex

There is no known dependence of pharmacokinetics of propranolol by sex in infants.

Race

There is little information on dependence of pharmacokinetics of propranolol by race in infants.

A study conducted in 12 Caucasian and 13 African-American adult male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.

Chinese adult subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha1 acid glycoprotein.

Drug Interaction Studies

Impact of propranolol on co-administered drugs: The effect of propranolol on plasma concentration of co-administered drug is presented in the table below.

Table 3. Effect of propranolol on co-administered drugs

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> <span class="Bold">Co-administered drug</span> </p> </td><td> <p class="First"> <span class="Bold">Effect on plasma concentration of co-administered drug</span> </p> </td> </tr> <tr> <td> <p class="First">Amide anesthetics (lidocaine, bupivacaine, mepivacaine)</p> </td><td> <p class="First">Increase</p> </td> </tr> <tr> <td> <p class="First">Warfarin</p> </td><td> <p class="First">Increase</p> </td> </tr> <tr> <td> <p class="First">Propafenone</p> </td><td> <p class="First">Increase &gt; 200 %</p> </td> </tr> <tr> <td> <p class="First">Nifedipine</p> </td><td> <p class="First">Increase 80 %</p> </td> </tr> <tr> <td> <p class="First">Verapamil</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Pravastatin, lovastatin</p> </td><td> <p class="First">Decrease 20%</p> </td> </tr> <tr> <td> <p class="First">Fluvastatin</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Zolmitriptan</p> </td><td> <p class="First">Increase 60 %</p> </td> </tr> <tr> <td> <p class="First">Rizatriptan</p> </td><td> <p class="First">Increase 80 %</p> </td> </tr> <tr> <td> <p class="First">Thioridazine</p> </td><td> <p class="First">Increase 370 %</p> </td> </tr> <tr> <td> <p class="First">Diazepam</p> </td><td> <p class="First">Increase</p> </td> </tr> <tr> <td> <p class="First">Oxazepam, triazolam, lorazepam, alprazolam</p> </td><td> <p class="First">No change</p> </td> </tr> <tr class="Last"> <td> <p class="First">Theophylline</p> </td><td> <p class="First">Increase 70 %</p> </td> </tr> </tbody> </table></div>

Impact of co-administered drugs on propranolol: The effect of co-administered drugs on propranolol plasma concentration is presented in the table below.

Table 4. Effect of co-administered drugs on propranolol

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <tbody class="Headless"> <tr class="First"> <td> <p class="First"> <span class="Bold">Co-administered drug</span> </p> </td><td> <p class="First"> <span class="Bold">Effect on propranolol plasma concentration</span> </p> </td> </tr> <tr> <td> <p class="First">CYP2D6, CYP1A2 or CYP2C19 inhibitors</p> </td><td> <p class="First">Increase</p> </td> </tr> <tr> <td> <p class="First">CYP1A2 or CYP2C19 inducers</p> </td><td> <p class="First">Decrease</p> </td> </tr> <tr> <td> <p class="First">Quinidine</p> </td><td> <p class="First">Increase &gt; 200 %</p> </td> </tr> <tr> <td> <p class="First">Nisoldipine</p> </td><td> <p class="First">Increase 50 %</p> </td> </tr> <tr> <td> <p class="First">Nicardipine</p> </td><td> <p class="First">Increase 80 %</p> </td> </tr> <tr> <td> <p class="First">Chlorpromazine</p> </td><td> <p class="First">Increase 70 %</p> </td> </tr> <tr> <td> <p class="First">Cimetidine</p> </td><td> <p class="First">Increase 50 %</p> </td> </tr> <tr> <td> <p class="First">Cholestyramine, colestipol</p> </td><td> <p class="First">Decrease 50 %</p> </td> </tr> <tr> <td> <p class="First">Alcohol</p> </td><td> <p class="First">Increase (acute use), decrease (chronic use)</p> </td> </tr> <tr> <td> <p class="First">Diazepam</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Verapamil</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Metoclopramide</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Ranitidine</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Lansoprazole</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Omeprazole</p> </td><td> <p class="First">No change</p> </td> </tr> <tr> <td> <p class="First">Propafenone</p> </td><td> <p class="First">Increase 200 %</p> </td> </tr> <tr class="Last"> <td> <p class="First">Aluminum hydroxide</p> </td><td> <p class="First">Decrease 50 %</p> </td> </tr> </tbody> </table></div>

In studies of mice and rats fed propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is about 3 and 7 times, respectively, the MRHD of 3.4 mg/kg/day propranolol hydrochloride in children.

Based on differing results from bacterial reverse mutation (Ames) tests performed by different laboratories, there is equivocal evidence for mutagenicity in one strain ( S. typhimurium strain TA 1538).

In a study in which both male and female rats were exposed to propranolol hydrochloride via diet at concentrations of up to 0.05% (about 50 mg/kg or less than the MRHD of 640 mg propranolol hydrochloride in adults) started from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. The potential effects of propranolol hydrochloride on fertility of juvenile rats were evaluated following daily oral administration from post-natal Day 4 (PND 4) to PND 21 at dose-levels of 0, 11.4, 22.8 or 45.6  mg/kg/day. No propranolol related effects on reproductive parameters or reproductive development were observed up to the highest dose level of 45.6 mg/kg/day, a dose that represents a systemic exposure of 3 times that seen in children at the MRHD.

This study in juvenile rats with propranolol hydrochloride described above was intended to cover the period of development corresponding to infancy, childhood and adolescence. Neurologic effects including hypoactivity and delayed air righting reflex, increased germinal centers of lymph nodes, and increased white blood cells and lymphocytes were seen at a propranolol hydrochloride dose 45.6 mg/kg/day that represents a systemic exposure of 3 times that seen in children at the MRHD.  Body weights were transiently decreased, and transient decreases in urine volume were associated with higher incidences of minimal renal cysts and dilation of kidney tubules at doses about equal to the MRHD in children.

A randomized, double-blind study in 460 infants, aged 35 days to 5 months at inclusion, with proliferating infantile hemangiomas (IH) requiring systemic therapy (excluding life-threatening IH, function-threatening IH, and ulcerated IH with pain and lack of response to simple wound care measures) compared four regimens of HEMANGEOL (1.2 or 3.4 mg/kg/day in twice daily divided doses for 3 or 6 months; N=99-103 per group) to placebo (N=55). Clinical efficacy was evaluated by counting complete or nearly complete resolution of the target hemangioma, which was evaluated by blinded centralized independent assessments of photographs at Week 24 compared to baseline.

{ "type": "p", "children": [], "text": "A randomized, double-blind study in 460 infants, aged 35 days to 5 months at inclusion, with proliferating infantile hemangiomas (IH) requiring systemic therapy (excluding life-threatening IH, function-threatening IH, and ulcerated IH with pain and lack of response to simple wound care measures) compared four regimens of HEMANGEOL (1.2 or 3.4 mg/kg/day in twice daily divided doses for 3 or 6 months; N=99-103 per group) to placebo (N=55). Clinical efficacy was evaluated by counting complete or nearly complete resolution of the target hemangioma, which was evaluated by blinded centralized independent assessments of photographs at Week 24 compared to baseline." }

Demographic patient characteristics and hemangioma characteristics were similar among the five regimens. For the whole population, 29% were male, 37% were in the lower age group (35-90 days), and 72% were Caucasian. Overall, 70% had a target hemangioma on the head, most commonly cheek (13%) and forehead (11%).

{ "type": "p", "children": [], "text": "Demographic patient characteristics and hemangioma characteristics were similar among the five regimens. For the whole population, 29% were male, 37% were in the lower age group (35-90 days), and 72% were Caucasian. Overall, 70% had a target hemangioma on the head, most commonly cheek (13%) and forehead (11%)." }

The main reason for treatment discontinuation was the treatment inefficacy, which happened in 58% of patients randomized to placebo, 25-30% of patients randomized to HEMANGEOL for 3 months (mainly after the switch to placebo), and 7-9% of patients randomized to HEMANGEOL for 6 months.

{ "type": "p", "children": [], "text": "The main reason for treatment discontinuation was the treatment inefficacy, which happened in 58% of patients randomized to placebo, 25-30% of patients randomized to HEMANGEOL for 3 months (mainly after the switch to placebo), and 7-9% of patients randomized to HEMANGEOL for 6 months. " }

Overall, 2 out of 55 patients (4%) in the placebo arm and 61 out of 101 patients (60%) on HEMANGEOL 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at Week 24 (p <0.0001).

{ "type": "p", "children": [], "text": "Overall, 2 out of 55 patients (4%) in the placebo arm and 61 out of 101 patients (60%) on HEMANGEOL 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at Week 24 (p <0.0001). " }

There were no significant differences in response by age (35-90 days / 91-150 days), sex, or hemangioma site. There were too few non-Caucasians to assess differences in effects by race.

{ "type": "p", "children": [], "text": "There were no significant differences in response by age (35-90 days / 91-150 days), sex, or hemangioma site. There were too few non-Caucasians to assess differences in effects by race. " }

Of patients on HEMANGEOL 3.4 mg/kg/day for 6 months who were considered successes, 10% required retreatment for recurrence of hemangiomas.

{ "type": "p", "children": [], "text": "Of patients on HEMANGEOL 3.4 mg/kg/day for 6 months who were considered successes, 10% required retreatment for recurrence of hemangiomas." }

A second uncontrolled study in 23 patients with proliferating IH included function-threatening IH, IH in certain anatomic locations that often leave permanent scars or deformity, large facial IH, smaller IH in exposed areas, severe ulcerated IH, pedunculated IH. Target lesions resolved in 36% of patients by 3 months.

{ "type": "p", "children": [], "text": "A second uncontrolled study in 23 patients with proliferating IH included function-threatening IH, IH in certain anatomic locations that often leave permanent scars or deformity, large facial IH, smaller IH in exposed areas, severe ulcerated IH, pedunculated IH. Target lesions resolved in 36% of patients by 3 months." }

HEMANGEOL is supplied as an oral solution. Each 1 mL contains 4.28 mg propranolol. HEMANGEOL is supplied in a carton containing one 120 mL bottle with syringe adapter and one 5-mL oral dosing syringe.

NDC 64370-375-01 Bottle 120 mL

Store at 25 °C (77 °F); excursions permitted from 15° to 30 °C (59° to 86 °F). [See USP Controlled Room Temperature.] Do not freeze. Do not shake the bottle before use. Dispense in original container with enclosed oral dosing syringe. The product can be kept for 2 months after first opening. See instructions for using enclosed oral dosing syringe.

See FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "See FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Patient advice

{ "type": "p", "children": [], "text": "\nPatient advice\n" }

Advise parents or caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise parents or caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Instructions for using oral dosing syringe

{ "type": "p", "children": [], "text": "\nInstructions for using oral dosing syringe\n" }

Instruct parents or caregivers on use of the oral dosing syringe.

{ "type": "p", "children": [], "text": "Instruct parents or caregivers on use of the oral dosing syringe." }

Risk of hypoglycemia

{ "type": "p", "children": [], "text": "\nRisk of hypoglycemia\n" }

Inform parents or caregivers that there is a risk of hypoglycemia while on HEMANGEOL. Hypoglycemia can occur at any time during treatment. Instruct caregivers to skip dosing in patients who are fasting (e.g., poor oral food intake, infection, vomiting), or when glucose demands are increased (e.g., cold, stress, infections). Instruct parents or caregivers how to recognize the signs of hypoglycemia. Tell them to discontinue HEMANGEOL if hypoglycemia develops and call their health care provider immediately or take the child to the emergency room. [see Warnings and Precautions 5.1]

{ "type": "p", "children": [], "text": "Inform parents or caregivers that there is a risk of hypoglycemia while on HEMANGEOL.\n \nHypoglycemia can occur at any time during treatment. Instruct caregivers to skip dosing in patients who are fasting (e.g., poor oral food intake, infection, vomiting), or when glucose demands are increased (e.g., cold, stress, infections). Instruct parents or caregivers how to recognize the signs of hypoglycemia. Tell them to discontinue HEMANGEOL if hypoglycemia develops and call their health care provider immediately or take the child to the emergency room. \n [see Warnings and Precautions 5.1]\n" }

Cardiovascular risks

{ "type": "p", "children": [], "text": "\nCardiovascular risks\n" }

Advise parents or caregivers that there is a potential risk for bradycardia, aggravation of pre-existing conduction disorders, and hypotension associated with the use of HEMANGEOL. Instruct them to contact their healthcare provider in case of fatigue, pallor, slow or uneven heart beats, peripheral coldness or fainting.

{ "type": "p", "children": [], "text": "Advise parents or caregivers that there is a potential risk for bradycardia, aggravation of pre-existing conduction disorders, and hypotension associated with the use of HEMANGEOL. Instruct them to contact their healthcare provider in case of fatigue, pallor, slow or uneven heart beats, peripheral coldness or fainting." }

Respiratory risks

{ "type": "p", "children": [], "text": "\nRespiratory risks\n" }

Inform parents or caregivers that HEMANGEOL carries risk of bronchospasm or exacerbation of lower respiratory tract infections. Instruct them to contact their healthcare provider or go to the nearest hospital emergency room if their child has breathing problems or wheezing during treatment with HEMANGEOL.

{ "type": "p", "children": [], "text": "Inform parents or caregivers that HEMANGEOL carries risk of bronchospasm or exacerbation of lower respiratory tract infections. Instruct them to contact their healthcare provider or go to the nearest hospital emergency room if their child has breathing problems or wheezing during treatment with HEMANGEOL." }

Other risks

{ "type": "p", "children": [], "text": "\nOther risks\n" }

Inform parents or caregivers that changes in sleep patterns may occur during HEMANGEOL therapy.

{ "type": "p", "children": [], "text": "Inform parents or caregivers that changes in sleep patterns may occur during HEMANGEOL therapy." }

Ask parents or caregivers to tell you all the medications they are administering to their child including prescription and over the counter medicines, vitamins, and herbal supplements. Ask breastfeeding mothers to tell you all the medications they are currently taking, as these may pass into the milk.

{ "type": "p", "children": [], "text": "Ask parents or caregivers to tell you all the medications they are administering to their child including prescription and over the counter medicines, vitamins, and herbal supplements. Ask breastfeeding mothers to tell you all the medications they are currently taking, as these may pass into the milk." }

MEDICATION GUIDE

{ "type": "p", "children": [], "text": "\nMEDICATION GUIDE\n" }

HEMANGEOL ® (he-man je-ohl)

{ "type": "p", "children": [], "text": "HEMANGEOL \n ® (he-man je-ohl)\n " }

(propranolol hydrochloride oral solution)

{ "type": "p", "children": [], "text": "(propranolol hydrochloride oral solution)" }

What is the most important information I should know about HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about HEMANGEOL?\n" }

HEMANGEOL can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nHEMANGEOL can cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nLow blood sugar (hypoglycemia), especially if your child is not taking feedings, or is vomiting. HEMANGEOL may make it more difficult to recognize the signs and symptoms of low blood sugar in your child.\n " ], "text": "" }

To help reduce the risk of low blood sugar with HEMANGEOL:

{ "type": "p", "children": [], "text": "\nTo help reduce the risk of low blood sugar with HEMANGEOL:\n" }

{ "type": "ul", "children": [ "Give HEMANGEOL during or shortly after feeding your child.", "Feed your child regularly during treatment. Tell your doctor if your child has a poor appetite.", "If your child is not taking feedings, for example, due to an illness or vomiting, do not give HEMANGEOL until your child is taking feedings normally again." ], "text": "" }

If your child has any of the signs or symptoms of low blood sugar listed below during treatment with HEMANGEOL, stop giving your child HEMANGEOL, call your healthcare provider immediately or go to the emergency room. If the child is conscious, give him/her a drink of liquid containing sugar.

{ "type": "p", "children": [], "text": "\nIf your child has any of the signs or symptoms of low blood sugar listed below during treatment with HEMANGEOL, stop giving your child HEMANGEOL, call your healthcare provider immediately or go to the emergency room. If the child is conscious, give him/her a drink of liquid containing sugar.\n" }

Signs or symptoms of low blood sugar include: pale, blue or purple skin color, sweating, irritability, crying for no apparent reason, irregular or fast heartbeat, poor feeding, low body temperature, unusual sleepiness, seizures, breathing stops for short periods of time, and loss of consciousness.

{ "type": "p", "children": [], "text": "\nSigns or symptoms of low blood sugar include: pale, blue or purple skin color, sweating, irritability, crying for no apparent reason, irregular or fast heartbeat, poor feeding, low body temperature, unusual sleepiness, seizures, breathing stops for short periods of time, and loss of consciousness.\n " }

What is HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWhat is HEMANGEOL?\n" }

HEMANGEOL is a prescription medicine used to treat proliferating infantile hemangioma that requires treatment with a medicine that spreads throughout the body.

{ "type": "p", "children": [], "text": "HEMANGEOL is a prescription medicine used to treat proliferating infantile hemangioma that requires treatment with a medicine that spreads throughout the body." }

Who should not take HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWho should not take HEMANGEOL?\n" }

Do not give HEMANGEOL to your child if your child:

{ "type": "p", "children": [], "text": "\nDo not give HEMANGEOL to your child if your child:\n" }

{ "type": "ul", "children": [ "was born prematurely and has not reached the corrected age of 5 weeks", "weighs less than 4 ½ pounds", "is allergic to propranolol or any of the other ingredients in HEMANGEOL. See the end of this Medication Guide for a list of ingredients in HEMANGEOL", "has asthma or a history of breathing problems", "has a heart problem, slow heart rate (less than 80 heart beats per minute), very low blood pressure", "is at risk for low blood sugar, for example is vomiting or unable to take feedings", "has high blood pressure caused by a tumor on the adrenal gland, called “pheochromocytoma”" ], "text": "" }

What should I tell my doctor before giving my child HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWhat should I tell my doctor before giving my child HEMANGEOL?\n" }

Before you start giving HEMANGEOL to your child, tell your child’s doctor about all of your child’s medical conditions.

{ "type": "p", "children": [], "text": "\nBefore you start giving HEMANGEOL to your child, tell your child’s doctor about all of your child’s\n \nmedical conditions.\n \n" }

Tell your doctor about all of the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. HEMANGEOL and some medicines may interact with each other and cause serious side effects. Especially tell your doctor if your child takes a steroid medicine. Taking a steroid medicine during treatment with HEMANGEOL may increase your child’s risk of low blood sugar.

{ "type": "p", "children": [], "text": "\nTell your doctor about all of the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements. HEMANGEOL and some medicines may interact with each other and cause serious side effects. Especially tell your doctor if your child takes a steroid medicine. Taking a steroid medicine during treatment with HEMANGEOL may increase your child’s risk of low blood sugar.\n " }

If you are breastfeeding your child, it is important to tell your doctor about all the medicines you take. Certain medicines may pass to your child through your breast-milk and interact with HEMANGEOL. Your doctor should tell you if you should stop breastfeeding.

{ "type": "p", "children": [], "text": "\nIf you are breastfeeding your child, it is important to tell your doctor about all the medicines you take. Certain medicines may pass to your child through your breast-milk and interact with HEMANGEOL. Your doctor should tell you if you should stop breastfeeding.\n " }

How should I give HEMANGEOL to my child?

{ "type": "p", "children": [], "text": "\nHow should I give HEMANGEOL to my child?\n" }

Follow the detailed Instructions for Use that come with HEMANGEOL for information about the correct way to prepare and give a dose of HEMANGEOL.

{ "type": "p", "children": [], "text": "\nFollow the detailed Instructions for Use that come with HEMANGEOL for information about the correct way to prepare and give a dose of HEMANGEOL.\n" }

{ "type": "ul", "children": [ "Give HEMANGEOL to your child exactly as your doctor tells you.", "Your doctor may change the dose until it is right for your child, and as your child’s weight changes.", "\nAlways give HEMANGEOL with a feeding or right away after a feeding.\n", "HEMANGEOL is given 2 times each day, at least 9 hours apart.", "If your child spits up a dose or if you are not sure your child got all of the medicine, do not give another dose. Wait until the next scheduled dose." ], "text": "" }

What are the possible side effects of HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of HEMANGEOL?\n" }

See “ What is the most important information I should know about HEMANGEOL?”

{ "type": "p", "children": [], "text": "See \n “ \n What is the most important information I should know about HEMANGEOL?” \n \n" }

HEMANGEOL can cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nHEMANGEOL can cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nNew or worsening slow heart rate (bradycardia) or low blood pressure (hypotension). Call your doctor if your child has any of these symptoms: pale skin color, slow or uneven heartbeats, arms or legs feel cold, blue or purple skin color, or fainting.\n ", "\nBreathing problems or wheezing. HEMANGEOL can cause spasms of your child’s airway. Call your doctor or go to the nearest hospital emergency room if your child has breathing problems or wheezing during treatment with HEMANGEOL.\n ", "\nStroke. HEMANGEOL may increase the risk of stroke in certain children who have severe problems with the blood vessels in their brain, particularly if your child has a large hemangioma that affects the face or head.\n " ], "text": "" }

The most common side effects include: sleep problems, worsening respiratory tract infections, diarrhea, and vomiting.

{ "type": "p", "children": [], "text": "\nThe most common side effects include: sleep problems, worsening respiratory tract infections, diarrhea, and vomiting.\n " }

These are not all the possible side effects of HEMANGEOL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of HEMANGEOL. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store HEMANGEOL?

{ "type": "p", "children": [], "text": "\nHow should I store HEMANGEOL?\n" }

{ "type": "ul", "children": [ "Store HEMANGEOL at room temperature between 68 \n o F to 77 \n o F (20 \n o C to 25 \n o C). Do not freeze. Do not shake before use.\n ", "Safely throw away any opened bottle of HEMANGEOL after 2 months, even if there is medicine left in the bottle." ], "text": "" }

Keep HEMANGEOL and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep HEMANGEOL and all medicines out of the reach of children.\n" }

General information about the safe and effective use of HEMANGEOL.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of HEMANGEOL.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about HEMANGEOL that is written for health professionals. Do not use HEMANGEOL for a condition for which it was not prescribed. Do not give HEMANGEOL to other people, even if they have the same symptoms your child has. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about HEMANGEOL that is written for health professionals. Do not use HEMANGEOL for a condition for which it was not prescribed. Do not give HEMANGEOL to other people, even if they have the same symptoms your child has. It may harm them." }

What are the ingredients in HEMANGEOL?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in HEMANGEOL?\n" }

Active ingredient: propranolol hydrochloride

{ "type": "p", "children": [], "text": "\nActive ingredient: propranolol hydrochloride\n " }

Inactive ingredients: strawberry flavor, vanilla flavor, hydroxyethylcellulose, saccharin sodium, citric acid monohydrate, and water.

{ "type": "p", "children": [], "text": "\nInactive ingredients: strawberry flavor, vanilla flavor, hydroxyethylcellulose, saccharin sodium, citric acid monohydrate, and water.\n " }

Manufactured for: Pierre Fabre Pharmaceuticals, Inc., Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Manufactured for: Pierre Fabre Pharmaceuticals, Inc., Parsippany, NJ 07054" }

For more information, call 1-855-PFPHARM (737-4276)

{ "type": "p", "children": [], "text": "For more information, call 1-855-PFPHARM (737-4276)" }

This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: Jun 2021

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration Issued: Jun 2021" }

Instructions for Use

{ "type": "p", "children": [], "text": "\nInstructions for Use\n" }

HEMANGEOL ® (he-man je-ohl)

{ "type": "p", "children": [], "text": "\nHEMANGEOL \n ® (he-man je-ohl) \n \n" }

(propranolol hydrochloride oral solution)

{ "type": "p", "children": [], "text": "\n(propranolol hydrochloride oral solution)\n" }

Read these Instructions for Use before giving a dose of HEMANGEOL to your child for the first time and each time you get a refill. There may be new information. Your doctor or pharmacist should show you how to correctly measure and give a dose of HEMANGEOL to your child before you give it for the first time.

{ "type": "p", "children": [], "text": "Read these Instructions for Use before giving a dose of HEMANGEOL to your child for the first time and each time you get a refill. There may be new information. Your doctor or pharmacist should show you how to correctly measure and give a dose of HEMANGEOL to your child before you give it for the first time." }

Important: Read the Medication Guide that comes with HEMANGEOL.

{ "type": "p", "children": [], "text": "\nImportant: \n Read the Medication Guide that comes with HEMANGEOL.\n" }

{ "type": "ul", "children": [ "To reduce the risk of your child getting low blood sugar (hypoglycemia), you must give HEMANGEOL either during a feeding or right away after a feeding.", "\nDo not give a dose of HEMANGEOL if your child is vomiting, is not taking feedings, or is showing signs or symptoms of low blood sugar. \n" ], "text": "" }

When you get HEMANGEOL from your doctor or pharmacist, you will receive a box that contains the supplies needed to give HEMANGEOL to your child, including:

{ "type": "p", "children": [], "text": "When you get HEMANGEOL from your doctor or pharmacist, you will receive a box that contains the supplies needed to give HEMANGEOL to your child, including:" }

{ "type": "ul", "children": [ "One glass bottle of HEMANGEOL", "One 5 mL oral dosing syringe (inside a plastic bag) that is marked to help you correctly measure a dose of HEMANGEOL ( \n See Figure A). If the carton does not contain the oral dosing syringe, ask your pharmacist to give you an oral dosing syringe that can be used to measure HEMANGEOL.\n " ], "text": "" }

Figure A

{ "type": "p", "children": [], "text": "\nFigure A\n" }

Preparing to give your child a dose of HEMANGEOL:

{ "type": "p", "children": [], "text": "\nPreparing to give your child a dose of HEMANGEOL:\n" }

Step 1. Place your box of supplies on a clean flat work surface, such as a table.

{ "type": "p", "children": [], "text": "\nStep 1. Place your box of supplies on a clean flat work surface, such as a table.\n " }

Step 2. Remove the HEMANGEOL bottle and oral dosing syringe from the box ( See Figure A above). Do not shake the bottle before use. Keep the box for storage.

{ "type": "p", "children": [], "text": "\nStep 2. Remove the HEMANGEOL bottle and oral dosing syringe from the box ( \n See Figure A above). \n Do not shake the bottle before use. Keep the box for storage.\n " }

Step 3. Remove the oral dosing syringe from the plastic bag. Safely throw the plastic bag away. The barrel of the syringe has markings in milliliters (mL). Look at the markings on the barrel of the oral dosing syringe and find the mL marking that matches the HEMANGEOL dose in mL prescribed by your doctor ( See Figure B).

{ "type": "p", "children": [], "text": "\nStep 3. Remove the oral dosing syringe from the plastic bag. Safely throw the plastic bag away. The barrel of the syringe has markings in milliliters (mL). Look at the markings on the barrel of the oral dosing syringe and find the mL marking that matches the HEMANGEOL dose in mL prescribed by your doctor ( \n See Figure B).\n " }

Figure B

{ "type": "p", "children": [], "text": "\nFigure B\n" }

Step 4. Open the bottle of HEMANGEOL by pushing down on the plastic cap while turning the cap to the left ( See Figure C).

{ "type": "p", "children": [], "text": "\nStep 4. Open the bottle of HEMANGEOL by pushing down on the plastic cap while turning the cap to the left ( \n See Figure C).\n " }

{ "type": "ul", "children": [ "Write down on the box the date when you first open the bottle." ], "text": "" }

Figure C

{ "type": "p", "children": [], "text": "\nFigure C\n" }

Step 5. Place the bottle on your work surface. Use one hand to hold the bottle upright.Use your other hand to insert the tip of the oral dosing syringe into the syringe adapter at the top of the bottle. Push the plunger all the way down ( See Figure D).

{ "type": "p", "children": [], "text": "\nStep 5. Place the bottle on your work surface. Use one hand to hold the bottle upright.Use your other hand to insert the tip of the oral dosing syringe into the syringe adapter at the top of the bottle. Push the plunger all the way down ( \n See Figure D).\n " }

{ "type": "ul", "children": [ "Do not remove the syringe adapter. If the syringe adapter is missing talk to your pharmacist." ], "text": "" }

Figure D

{ "type": "p", "children": [], "text": "\nFigure D\n" }

Step 6: Use one hand to hold the oral dosing syringe in place. With your other hand, turn the bottle upside down. Pull back on the plunger until the top of the plunger lines up with the marking on the barrel of the syringe that matches the dose of HEMANGEOL prescribed by your doctor ( See Figure E). Your child’s dose may be different than the dose shown in Figure E.

{ "type": "p", "children": [], "text": "\nStep 6: Use one hand to hold the oral dosing syringe in place. With your other hand, turn the bottle upside down. Pull back on the plunger until the top of the plunger lines up with the marking on the barrel of the syringe that matches the dose of HEMANGEOL prescribed by your doctor ( \n See Figure E). Your child’s dose may be different than the dose shown in Figure E.\n " }

Figure E

{ "type": "p", "children": [], "text": "\nFigure E\n" }

Step 7: Check for air bubbles in the oral dosing syringe. If you see air bubbles, push up on the plunger towards the bottle just enough to remove any large air bubbles and then pull back to the measured dose ( See Figure F).

{ "type": "p", "children": [], "text": "\nStep 7: Check for air bubbles in the oral dosing syringe. If you see air bubbles, push up on the plunger towards the bottle just enough to remove any large air bubbles and then pull back to the measured dose ( \n See Figure F).\n " }

Figure F

{ "type": "p", "children": [], "text": "\nFigure F\n" }

Step 8. Turn bottle upright again and place it in on your work surface. Remove the oral dosing syringe from the bottle ( See Figure G). Do not push the plunger in during this step. The syringe adapter should stay attached to the bottle.

{ "type": "p", "children": [], "text": "\nStep 8. Turn bottle upright again and place it in on your work surface. Remove the oral dosing syringe from the bottle ( \n See Figure G). Do not push the plunger in during this step. The syringe adapter should stay attached to the bottle.\n " }

Figure G

{ "type": "p", "children": [], "text": "\nFigure G\n" }

Giving your child a dose of HEMANGEOL:

{ "type": "p", "children": [], "text": "\nGiving your child a dose of HEMANGEOL:\n" }

Step 9. Slowly squirt HEMANGEOL into your child’s mouth after placing the oral dosing syringe against the inside of the cheek ( See Figure H).

{ "type": "p", "children": [], "text": "\nStep 9. Slowly squirt HEMANGEOL into your child’s mouth after placing the oral dosing syringe against the inside of the cheek ( \n See Figure H).\n " }

{ "type": "ul", "children": [ "Keep your child in an upright position for a few minutes right after giving a dose of HEMANGEOL." ], "text": "" }

Figure H

{ "type": "p", "children": [], "text": "\nFigure H\n" }

{ "type": "ul", "children": [ "If needed, you can dilute the dose of HEMANGEOL in a small amount of milk or fruit juice and give it to your child in a baby’s bottle. If your child spits up a dose or if you are not sure your child got all of the medicine, do not give another dose. Wait until the next scheduled dose." ], "text": "" }

Step 10. Replace the plastic cap on the bottle. Close the bottle by turning the plastic cap to the right ( See Figure I).

{ "type": "p", "children": [], "text": "\nStep 10. Replace the plastic cap on the bottle. Close the bottle by turning the plastic cap to the right ( \n See Figure I).\n " }

Figure I

{ "type": "p", "children": [], "text": "\nFigure I\n" }

Cleaning the oral dosing syringe:

{ "type": "p", "children": [], "text": "\nCleaning the oral dosing syringe:\n" }

Step 11: Clean the oral dosing syringe after each use by rinsing with clean tap water ( See Figure J).

{ "type": "p", "children": [], "text": "\nStep 11: Clean the oral dosing syringe after each use by rinsing with clean tap water ( \n See Figure J).\n " }

{ "type": "ul", "children": [ "Do not take apart the oral dosing syringe.", "Do not use any soap or alcohol based product to clean. Wipe the outside dry.", "Do not put the oral dosing syringe through a sterilizer or dishwasher." ], "text": "" }

Figure J

{ "type": "p", "children": [], "text": "\nFigure J\n" }

Step 12: Place the bottle and the oral dosing syringe in the box.

{ "type": "p", "children": [], "text": "\nStep 12: Place the bottle and the oral dosing syringe in the box.\n " }

How should I store HEMANGEOL?

{ "type": "p", "children": [], "text": "\nHow should I store HEMANGEOL?\n" }

{ "type": "ul", "children": [ "When not in use, keep the bottle of HEMANGEOL and the oral dosing syringe in the box it comes in.", "Store HEMANGEOL at room temperature, between 68 \n o F to 77 \n o F (20 \n o C to 25 \n o C). Do not freeze.\n ", "Safely throw away any opened bottle of HEMANGEOL after 2 months, even if there is medicine left in the bottle." ], "text": "" }

Keep HEMANGEOL and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep HEMANGEOL and all medicines out of the reach of children.\n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "\nThis Instructions for Use has been approved by the U.S. Food and Drug Administration.\n" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Pierre Fabre Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "Pierre Fabre Pharmaceuticals, Inc." }

Parsippany, NJ 07054

{ "type": "p", "children": [], "text": "Parsippany, NJ 07054" }

PRINCIPAL DISPLAY PANEL - 120 mL Bottle Label 

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - 120 mL Bottle Label  \n" }

NDC 64370-375-01

{ "type": "p", "children": [], "text": "NDC 64370-375-01" }

Hemangeol ®

{ "type": "p", "children": [], "text": "\nHemangeol\n \n \n ®\n" }

(propranolol hydrochloride)

{ "type": "p", "children": [], "text": "(propranolol hydrochloride)" }

oral solution

{ "type": "p", "children": [], "text": "oral solution" }

4.28 mg/mL

{ "type": "p", "children": [], "text": "\n4.28 mg/mL\n" }

Dispense with enclosed Medication Guide

{ "type": "p", "children": [], "text": "\nDispense with enclosed Medication Guide\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

120 mL

{ "type": "p", "children": [], "text": "120 mL" }

PRINCIPAL DISPLAY PANEL - 120 mL Carton Label

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - 120 mL Carton Label \n" }

NDC 64370-375-01

{ "type": "p", "children": [], "text": "NDC 64370-375-01" }

Hemangeol ®

{ "type": "p", "children": [], "text": "\nHemangeol\n \n \n ®\n" }

(propranolol hydrochloride)

{ "type": "p", "children": [], "text": "(propranolol hydrochloride)" }

oral solution

{ "type": "p", "children": [], "text": "oral solution" }

4.28 mg/mL

{ "type": "p", "children": [], "text": "\n4.28 mg/mL\n" }

Pharmacist: Dispense the enclosed Medication Guide to each patient

{ "type": "p", "children": [], "text": "\nPharmacist: Dispense the enclosed Medication Guide to each patient\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

120 mL

{ "type": "p", "children": [], "text": "120 mL" }

INDERAL XL is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including beta-blockers.

{ "type": "p", "children": [], "text": "INDERAL XL is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including beta-blockers. " }

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

{ "type": "p", "children": [], "text": "Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)." }

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

{ "type": "p", "children": [], "text": "Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly." }

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

{ "type": "p", "children": [], "text": "Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal." }

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

{ "type": "p", "children": [], "text": "Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy." }

INDERAL XL should be administered once daily at bedtime and should be taken consistently either on an empty stomach or with food. Initiate dosing at 80 mg and titrate to 120 mg daily as needed for blood pressure control. Doses above 120 mg have no additional effects on blood pressure [see Clinical Studies (14.1)]. Full antihypertensive response is usually achieved within 2 to 3 weeks.

{ "type": "p", "children": [], "text": "INDERAL XL should be administered once daily at bedtime and should be taken consistently either on an empty stomach or with food. Initiate dosing at 80 mg and titrate to 120 mg daily as needed for blood pressure control. Doses above 120 mg have no additional effects on blood pressure [see Clinical Studies (14.1)]. Full antihypertensive response is usually achieved within 2 to 3 weeks." }

INDERAL XL Extended-Release Capsules are supplied as capsules containing either 80 mg (equivalent to 70.14 mg of propranolol) or 120 mg (equivalent to 105.21 mg of propranolol) of propranolol hydrochloride imprinted with “Inderal XL” using FD&C Blue #2 Aluminum Lake. In addition, the 80 mg strength is a white opaque capsule, imprinted with “80” and 1 segmented band, while the 120 mg strength is a buff opaque capsule imprinted with “120” and 3 segmented bands.

{ "type": "p", "children": [], "text": "INDERAL XL Extended-Release Capsules are supplied as capsules containing either 80 mg (equivalent to 70.14 mg of propranolol) or 120 mg (equivalent to 105.21 mg of propranolol) of propranolol hydrochloride imprinted with “Inderal XL” using FD&C Blue #2 Aluminum Lake. In addition, the 80 mg strength is a white opaque capsule, imprinted with “80” and 1 segmented band, while the 120 mg strength is a buff opaque capsule imprinted with “120” and 3 segmented bands." }

INDERAL XL is contraindicated in patients with:

{ "type": "p", "children": [], "text": "INDERAL XL is contraindicated in patients with:" }

{ "type": "", "children": [], "text": "" }

Following abrupt discontinuation of therapy with beta-blockers, exacerbations of angina pectoris and myocardial infarction have occurred.

When discontinuing chronically administered INDERAL XL, particularly in patients with ischemic heart disease, gradually reduce the dose over a period of 1-2 weeks and monitor the patients. If angina markedly worsens or acute coronary insufficiency develops, promptly resume therapy, at least temporarily and take other measures appropriate for the management of unstable angina. Warn patients against interruption or discontinuation of therapy without physician’s advice.

Because coronary artery disease is common and may be unrecognized, avoid abrupt discontinuation of INDERAL XL therapy even in patients treated only for hypertension.

Beta-blockers, like INDERAL XL, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. If signs or symptoms of heart failure develop, treat the patient according to recommended guidelines. It may be necessary to lower the dose of INDERAL XL or to discontinue it.

Chronically administered beta-blocking therapy, including INDERAL XL, should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

INDERAL XL may mask clinical signs of hyperthyroidism, such as tachycardia. Avoid abrupt withdrawal of beta-blockade, which may precipitate a thyroid storm.

Bradycardia, including sinus pause, heart block, and cardiac arrest have occurred with the use of INDERAL XL. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders (including Wolff-Parkinson-White) may be at increased risk. The concomitant use of beta-adrenergic blockers and non-dihydropyridine calcium channel blockers (e.g., verapamil and diltiazem), digoxin or clonidine increases the risk of significant bradycardia. Monitor heart rate and rhythm in patients receiving INDERAL XL. If severe bradycardia develops, reduce or stop INDERAL XL.

Beta-adrenergic blocker-treated patients treated with epinephrine for a severe anaphylactic reaction may be less responsive to the typical doses of epinephrine. In these patients, consider other medications (e.g., intravenous fluids, glucagon).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions occurring at a rate of ≥3%, excluding those reported more commonly in placebo, encountered in the INDERAL XL placebo-controlled hypertension trials and plausibly related to treatment are shown in Table 1.

Table 1. Treatment-Emergent Adverse Reactions Reported In ≥3% of Subjects

<div class="scrollingtable"><table width="100%"> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <span class="Bold">INDERAL XL</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Body System</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo (N=88)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">80 mg (N=89)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">120mg (N=85)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Fatigue</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (3%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">4 (5%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Dizziness (except vertigo)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">2 (2%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">6 (7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (4%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">3 (3%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">1 (1%)</p> </td> </tr> </tbody> </table></div>

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-marketing use of INDERAL XL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions were observed and have been reported with use of formulations of sustained- or immediate-release propranolol.

Allergic: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions; pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Autoimmune: Systemic lupus erythematosus (SLE).

Cardiovascular: exacerbation of peripheral arterial disease, arterial insufficiency, usually of the Raynaud type.

Central Nervous System: Light-headedness, mental depression, insomnia, lassitude, weakness, fatigue, visual disturbances, hallucinations, vivid dreams, short-term memory loss, emotional lability, slightly clouded sensorium, paresthesia of hands.

Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, mesenteric arterial thrombosis, ischemic colitis.

Genitourinary: Male impotence; Peyronie’s disease.

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Musculoskeletal: Myopathy, myotonia.

Skin and mucous membranes: Stevens-Johnson syndrome, toxic epidermal necrolysis, dry eyes, exfoliative dermatitis, erythema multiforme, urticaria, alopecia, SLE-like reactions, and psoriasisiform rashes.

Impact of Propranolol on Other Drugs

Warfarin: Warfarin concentrations are increased when administered with propranolol. Monitor prothrombin time accordingly [see Clinical Pharmacology (12.7)].

Propafenone: Co-administration of propranolol increases the plasma concentrations of propafenone. Monitor patients for symptoms of excessive exposure to propafenone including bradycardia and postural hypotension [see Clinical Pharmacology (12.7)].

Impact of Other Drugs on Propranolol

CYP2D6, CYP1A2 and CYP2C19 Inhibitors: CYP2D6 inhibitors (e.g. bupropion, fluoxetine, paroxetine, quinidine), CYP1A2 inhibitors (e.g., ciprofloxacin, enoxamine, fluvoxamine) and CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) increase exposure to propranolol when co-administered with INDERAL XL. Monitor patients for bradycardia and hypotension [see Clinical Pharmacology (12.7)].

CYP1A2 and CYP2C19 Inducers: CYP1A2 inducers (e.g., phenytoin, montelukast, smoking) and CYP2C19 inducers (e.g. rifampin) decrease the plasma levels of propranolol resulting in a loss of efficacy [see Clinical Pharmacology (12.7)].

Cholestyramine and Colestipol: Co-administered cholestyramine or colestipol significantly reduces the plasma concentrations of co-administered propranolol which may result in loss of efficacy [see Clinical Pharmacology (12.7)].

Adrenergic Agonists: Beta-blockers may antagonize the antihypertensive effects of clonidine, and rebound hypertension may result if clonidine is withdrawn abruptly. If clonidine and a beta-blocker are co-administered, withdraw the beta-blocker several days before the withdrawal of clonidine.

Alpha Blockers: Co-administration of beta-blockers with alpha-blocker (e.g., prazosin) has been associated with prolongation of first dose hypotension and syncope.

Dobutamine: Propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.

Antidepressants: The hypotensive effect of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers. Monitor patients for postural hypotension.

Nonsteroidal Anti-Inflammatory Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-adrenoreceptor blocking agents. Monitor blood pressure.

Risk Summary

Prolonged experience with propranolol in pregnant women over several decades, based on published interventional and observational studies, has not identified a drug associated risk of major birth defects, miscarriage, or other adverse maternal outcomes. Bradycardia, hypoglycemia, and respiratory depression have been observed with use of beta-blockers, including propranolol, in utero near the time of delivery. There are inconsistent reports of intrauterine growth restriction with beta-blocker use, including propranolol, during pregnancy. Untreated hypertension during pregnancy can lead to serious adverse outcomes for the mother and the fetus (see Clinical Considerations and Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage) Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Propranolol crosses the placenta. Neonates born to mothers who are receiving propranolol during pregnancy, may be at risk for bradycardia, hypoglycemia, and respiratory depression. Monitor neonates exposed to propranolol during pregnancy and manage accordingly.

Data

Animal Data

In a series of reproductive and developmental toxicology studies, propranolol was given to rats by gavage or in the diet throughout pregnancy and lactation. At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the maximum recommended human oral daily dose (MRHD) on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol HCl was also administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the MRHD). No evidence of embryo or neonatal toxicity was noted.

Risk Summary

Propranolol is present in human milk at low levels, but the related risk to a breastfed infant is unknown. There are no data on the effects of propranolol on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INDERAL XL and any potential adverse effects on the breastfed child from INDERAL XL or from the underlying maternal condition.

Infertility

Males

Based on the published literature, beta-blockers, including propranolol, may cause erectile dysfunction. In rats, propranolol inhibits spermatogenesis [see Nonclinical Toxicology (13.1)].

Safety and effectiveness of propranolol in pediatric patients have not been established.

Clinical studies of INDERAL XL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The exposure to propranolol is increased in patients with renal impairment. Initiate INDERAL XL therapy in patients with impaired renal function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension [see Clinical Pharmacology (12.6)].

The exposure to propranolol is increased in patients with hepatic impairment. Initiate INDERAL XL therapy in patients with impaired hepatic function at the lowest dose (80 mg) once daily and monitor patients for marked bradycardia and hypotension [see Clinical Pharmacology (12.6)].

Most overdoses of propranolol are mild and respond to supportive care.

{ "type": "p", "children": [], "text": "Most overdoses of propranolol are mild and respond to supportive care. " }

Propranolol is not significantly dialyzable.

{ "type": "p", "children": [], "text": "Propranolol is not significantly dialyzable." }

Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.

{ "type": "p", "children": [], "text": "Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately. Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose. " }

Glucagon should be administered as 50 to 150 mcg/kg intravenously followed by continuous drip of 1 to 5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing.

{ "type": "p", "children": [], "text": "Glucagon should be administered as 50 to 150 mcg/kg intravenously followed by continuous drip of 1 to 5 mg/hour for positive chronotropic effect. Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful. Epinephrine, however, may provoke uncontrolled hypertension. Bradycardia can be treated with atropine or isoproterenol. Serious bradycardia may require temporary cardiac pacing." }

Monitor the electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance. Isoproterenol and aminophylline may be used for bronchospasm.

{ "type": "p", "children": [], "text": "Monitor the electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance. Isoproterenol and aminophylline may be used for bronchospasm." }

INDERAL XL contains propranolol hydrochloride, a nonselective, beta-adrenergic receptor-blocking agent for oral administration, as an extended-release product. INDERAL XL capsules contain sustained-release beads. Each of the beads contains propranolol hydrochloride and is coated with dual membranes. These membranes are designed to retard release of propranolol hydrochloride for several hours after ingestion followed by the sustained release of propranolol.

{ "type": "p", "children": [], "text": "INDERAL XL contains propranolol hydrochloride, a nonselective, beta-adrenergic receptor-blocking agent for oral administration, as an extended-release product. INDERAL XL capsules contain sustained-release beads. Each of the beads contains propranolol hydrochloride and is coated with dual membranes. These membranes are designed to retard release of propranolol hydrochloride for several hours after ingestion followed by the sustained release of propranolol." }

INDERAL XL is available as 80 mg and 120 mg capsules for oral administration.

{ "type": "p", "children": [], "text": "INDERAL XL is available as 80 mg and 120 mg capsules for oral administration." }

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The active ingredient in INDERAL XL is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:

{ "type": "p", "children": [], "text": "The active ingredient in INDERAL XL is a synthetic beta-adrenergic receptor-blocking agent chemically described as 1-(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:" }

Propranolol hydrochloride is a stable, white, crystalline solid, which is readily soluble in water and ethanol. Its molecular weight is 295.81. Each capsule for oral administration contains sugar spheres, ethylcellulose, povidone, hypromellose phthalate, diethyl phthalate, hypromellose, polyethylene glycol, gelatin, titanium dioxide. The ink contains FD&C Blue #2 Aluminum Lake. In addition, INDERAL XL 120 mg capsules contain yellow iron oxide.

{ "type": "p", "children": [], "text": "Propranolol hydrochloride is a stable, white, crystalline solid, which is readily soluble in water and ethanol. Its molecular weight is 295.81. Each capsule for oral administration contains sugar spheres, ethylcellulose, povidone, hypromellose phthalate, diethyl phthalate, hypromellose, polyethylene glycol, gelatin, titanium dioxide. The ink contains FD&C Blue #2 Aluminum Lake. In addition, INDERAL XL 120 mg capsules contain yellow iron oxide." }

The mechanism of the antihypertensive effect of propranolol has not been established. Among factors that contribute to the antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use. Effects of propranolol on plasma volume appear to be minor and somewhat variable.

Propranolol is a nonselective, beta-adrenergic receptor-blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor-stimulating agents for available receptor sites. Of the 2 enantiomers of propranolol, the S-enantiomer blocks beta-adrenergic receptors. When access to beta-receptor sites is blocked by propranolol, chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta-blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.

Absorption: Propranolol is highly lipophilic and is almost completely absorbed after oral administration. However, it undergoes high first-pass metabolism by the liver, and, on average, only about 25% of propranolol reaches the systemic circulation.

A single-dose, food-effect study in 36 healthy subjects showed that a high fat meal administered with INDERAL XL at 10 p.m., increased the lag time from 3 to 5 hours and the time to reach the maximum concentration from 11.5 to 15.4 hours, with no effect on the AUC.

Following multiple-dose administration of INDERAL XL at 10 p.m. under fasting conditions, the steady state lag time was between 4 and 5 hours and propranolol peak plasma concentrations were reached approximately 12 to 14 hours after dosing. Propranolol trough levels were achieved 24 to 27 hours after dosing, and persisted for 3 to 5 hours after the next dose.

The plasma levels of propranolol showed dose-proportional increases after single and multiple administration of 80, 120, and 160 mg of INDERAL XL.

At steady state, the bioavailability of a 160 mg dose of INDERAL XL and propranolol hydrochloride long-acting capsules did not differ significantly.

Distribution: Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S-isomer is preferentially bound to alpha1 glycoprotein and the R-isomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters.

Metabolism and Elimination: Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through 3 primary routes: Aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41%, and 17%, respectively, but with considerable variability between individuals. The 4 major metabolites are propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4-hydroxy propranolol.

In vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy propranolol is a weak inhibitor of CYP2D6.

Propranolol is also a substrate for CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.

In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance to 4-hydroxy propranolol was significantly higher and to naphthyloxylactic acid was significantly lower in EMs than PMs.

In normal subjects receiving oral doses of racemic propranolol, S-enantiomer concentrations exceeded those of the R-enantiomer by 40 to 90% as a result of stereoselective hepatic metabolism.

The elimination half-life of propranolol was approximately 8 hours.

Pediatric: The pharmacokinetics of INDERAL XL have not been investigated in patients younger than 18 years of age.

Geriatric: The pharmacokinetics of INDERAL XL have not been investigated in patients older than 65 years. In a study of 12 elderly (62 to 79 years old) and 12 young (25 to 33 years old) healthy subjects administered immediate-release propranolol, the clearance of the S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-lives of both R- and S-propranolol were prolonged in the elderly compared with the young (11 hours versus 5 hours).

Gender: In a dose-proportionality study, the pharmacokinetics of INDERAL XL were evaluated in 22 male and 14 female healthy volunteers. Following single doses under fasting conditions, the mean AUC and Cmax were about 49% and 16% higher for females across the dosage range. The mean elimination half-life was longer in females than in males (11 hours versus 7.5 hours).

Race: A study conducted in 12 white and 13 African-American male subjects taking immediate-release propranolol showed, at steady state, the clearance of R- and S-propranolol were about 76% and 53% higher in African-Americans than in whites, respectively.

Renal Impairment: The pharmacokinetics of propranolol after administration of INDERAL XL have not been evaluated in patients with renal impairment. In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (Cmax) of propranolol in the chronic renal failure group were 3- to 5-fold (161±41 ng/mL) those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure.

Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity.

Propranolol is not significantly dialyzable.

Hepatic Impairment: The pharmacokinetics of propranolol after administration of INDERAL XL have not been evaluated in patients with hepatic impairment. However, propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80 mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was 3-fold that of controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours.

Impact of Propranolol on Other Drugs

The effect of propranolol on exposure to other drugs is shown in Table 2.

Table 2 Impact of propranolol on other drugs

<div class="scrollingtable"><table width="100%"> <col width="57%"/> <col width="28%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Other drug</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Effect on their exposure</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Amide anesthetics (lidocaine, bupivacaine, mepivicaine)</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Warfarin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Propafenone</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased &gt;200%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nifedipine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 80%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Verapamil</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Pravastatin, lovastatin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased 20%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fluvastatin</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Zolmitriptan</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 60%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rizatriptan</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 80%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Thioridazine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 370%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diazepam</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Oxazepam, triazolam, lorazepam, alprazolam</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Theophylline</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 70%</p> </td> </tr> </tbody> </table></div>

Impact of Other Drugs on Propranolol

The effect of propranolol on exposure to other drugs is shown in Table 3.

Table 3 Impact of other drugs on exposure to propranolol

<div class="scrollingtable"><table width="100%"> <col width="48%"/> <col width="41%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Other drug</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Effect on propranolol exposure</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Inhibitors of CYP2D6, CYP1A2, or CYP2C19 </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Inducers of CYP1A2 or CYP2C19</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quinidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased &gt;200%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nisoldipine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 50%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nicardipine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 80%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Chlorpromazine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 70%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cimetidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 50%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cholestyramine, colestipol</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased 50%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alcohol</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diazepam</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Verapamil</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Metoclopramide</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Ranitidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Lansoprazole</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Omeprazole</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alcohol</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increase acutely or decrease chronically</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Propafenone</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 200%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Quinidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 200%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cimetidine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 40%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Aluminum hydroxide</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Decreased 50%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Diazepam</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">None</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Nisoldipine, nicardipine, nifedipine</p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Increased 50-80%</p> </td> </tr> </tbody> </table></div>

Carcinogenesis

In dietary administration studies in which mice and rats were treated with propranolol HCl for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the MRHD of 640 mg propranolol HCl.

Mutagenesis

Based on differing results from Ames tests performed by different laboratories, a genotoxic effect of propranolol HCl is equivocal in bacteria (S. typhimurium strain TA 1538).

Impairment of Fertility

Propranolol effects on fertility are also equivocal. No effects on fertility were reported in a study with both male and female rats exposed to propranolol HCl in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), from 60 days prior to mating and throughout pregnancy and lactation for 2 generations. Another study in rats receiving oral propranolol (7.5 and 15 mg/kg for 60 days) reported decreased sperm motility, increased sperm abnormalities and decreased testosterone; all effects were fully reversible within 60 days of propranolol discontinuation. A separate study in male mice receiving oral propranolol (10 or 15 mg/kg body weight) in water once daily reported both doses impaired spermatogenesis and reduced sperm motility; fewer females became pregnant and pregnant females had fewer implantation sites and viable fetuses. In addition, when female rabbits were injected with 7 mg/kg propranolol at three-hour intervals (8 times daily is about twice the MHRD), sperm counts in the oviducts were reduced and fewer sperm attached to and penetrated the eggs.

In a double-blind, parallel dose-response study in patients with mild-to-moderate hypertension (n=434), doses of INDERAL XL from 80 to 640 mg were taken once daily at approximately 10 p.m. INDERAL XL significantly lowered sitting systolic and diastolic blood pressure when measurements were taken approximately 16 hours later. The placebo-subtracted diastolic blood pressure effect for the 80- and 120-mg doses was -3.0 and -4.0 mm Hg, respectively. Higher doses of INDERAL XL (160, 640 mg) had no additional blood-pressure lowering effect when compared with 120 mg. The antihypertensive effects of INDERAL XL were seen in the elderly (≥65 years old) and men and women. There were too few non-white patients to assess the efficacy of INDERAL XL in these patients.

INDERAL XL (propranolol hydrochloride) Extended-Release Capsules are available as follows:

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Each white opaque capsule, imprinted with ‘Inderal XL’, ‘80’, and 1 segmented band, contains 80 mg of propranolol hydrochloride USP (equivalent to 70.14 mg of propranolol) and are available as follows: Bottles of 30          NDC 62559-600-30Bottles of 7            NDC 62559-600-77 (professional sample)Bottles of 14          NDC 62559-600-14 (professional sample).

{ "type": "p", "children": [], "text": "Each white opaque capsule, imprinted with ‘Inderal XL’, ‘80’, and 1 segmented band, contains 80 mg of propranolol hydrochloride USP (equivalent to 70.14 mg of propranolol) and are available as follows: Bottles of 30          NDC 62559-600-30Bottles of 7            NDC 62559-600-77 (professional sample)Bottles of 14          NDC 62559-600-14 (professional sample). " }

Each buff opaque capsule, imprinted with ‘Inderal XL’, ‘120’, and 3 segmented bands, contains 120 mg of propranolol hydrochloride USP (equivalent to 105.21 mg of propranolol) and are available as follows: Bottles of 30          NDC 62559-601-30Bottles of 7            NDC 62559-601-77 (professional sample)Bottles of 14          NDC 62559-601-14 (professional sample).

{ "type": "p", "children": [], "text": "Each buff opaque capsule, imprinted with ‘Inderal XL’, ‘120’, and 3 segmented bands, contains 120 mg of propranolol hydrochloride USP (equivalent to 105.21 mg of propranolol) and are available as follows: Bottles of 30          NDC 62559-601-30Bottles of 7            NDC 62559-601-77 (professional sample)Bottles of 14          NDC 62559-601-14 (professional sample)." }

Storage: Store at 25ºC (77ºF); excursions permitted to 15º and 30ºC (59º and 86ºF) [see USP Controlled Room Temperature] in a tightly closed container.

{ "type": "p", "children": [], "text": "\nStorage: Store at 25ºC (77ºF); excursions permitted to 15º and 30ºC (59º and 86ºF) [see USP Controlled Room Temperature] in a tightly closed container." }

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For further product information, please visit www.anipharmaceuticals.com or call 1-800-308-6755.

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Distributed by:ANI Pharmaceuticals, Inc.Baudette, MN 56623

{ "type": "p", "children": [], "text": "Distributed by:ANI Pharmaceuticals, Inc.Baudette, MN 56623\n" }

INDERAL XL®, a DIFFUCAPS® drug delivery product manufactured by Adare Pharmaceuticals, Inc., Vandalia, OH 45377

{ "type": "p", "children": [], "text": "INDERAL XL®, a DIFFUCAPS® drug delivery product manufactured by Adare Pharmaceuticals, Inc., Vandalia, OH 45377" }

10050 Rev 06/23

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INDERAL® XL (propranolol hydrochloride) Extended Release Capsules, 80 mgNDC 62559-600-30Rx only30 Capsules

{ "type": "p", "children": [], "text": "\nINDERAL® XL (propranolol hydrochloride) Extended Release Capsules, 80 mgNDC 62559-600-30Rx only30 Capsules\n" }

INDERAL® XL (propranolol hydrochloride) Extended Release Capsules, 120 mgNDC 62559-601-30Rx only30 Capsules

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