FDA label 249c9738-7dfa-4f18-8330-be14437da235

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions may occur. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions following discontinuation of administration ( 5.1 ). Thrombotic events have occurred in patients receiving off-label high doses of Berinert. Monitor patients with known risk factors for thrombotic events ( 5.2 ). Berinert is made from human plasma and may contain infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent ( 5.3 ). 5.1 Hypersensitivity Severe hypersensitivity reactions may occur. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction (see Patient Counseling Information [17] ). The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of Berinert. Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered. In case of suspected hypersensitivity, immediately discontinue administration of Berinert and institute appropriate treatment. 5.2 Thrombotic Events Thrombotic events have been reported in association with Berinert when used off-label and at higher than labeled doses. 1 Animal studies have confirmed the risk of thrombosis from intravenous administration of C1 esterase inhibitor products 2 ( see Overdosage [10] and Animal Toxicology and/or Pharmacology [13.2] ). 5.3 Transmission of Infectious Agents Because Berinert is made from human blood, it may contain infectious agents (eg, viruses and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by processes demonstrated to inactivate and/or remove certain viruses during manufacturing ( see Description [11] and Patient Counseling Information [17] ). Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Since 1979, a few suspected cases of viral transmission have been reported with the use of Berinert outside the US, including cases of acute hepatitis C. From the incomplete information available from these cases, it was not possible to determine with certainty if the infections were or were not related to prior administration of Berinert. The physician should discuss the risks and benefits of this product with the patient before prescribing or administering it to the patient. (See Patient Counseling Information [17.1] ). All infections thought by a physician possibly to have been transmitted by Berinert should be reported by lot number, by the physician, or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958.

6 ADVERSE REACTIONS The most serious adverse reaction reported in subjects enrolled in clinical studies who received Berinert was an increase in the severity of pain associated with HAE. The most common adverse reactions that have been reported in greater than 4% of the subjects who received Berinert in clinical studies were subsequent HAE attack, headache, abdominal pain, nausea, muscle spasm, pain, diarrhea and vomiting. The most serious adverse reaction reported in subjects who received Berinert was an increase in the severity of pain associated with HAE ( 6.1 ). The most common adverse reactions observed by ≥4% of subjects after Berinert treatment were subsequent HAE attack, headache, abdominal pain, nausea, muscle spasm, pain, diarrhea and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies 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. Placebo-controlled Clinical Study In the placebo-controlled clinical study, referred to as the randomized clinical trial (RCT) ( see Clinical Studies [14] ), 124 subjects experiencing an acute moderate to severe abdominal or facial HAE attack were treated with Berinert (either a 10 unit per kg body weight or a 20 unit per kg body weight dose), or placebo (physiological saline solution). The treatment-emergent serious adverse reactions/events that occurred in 5 subjects in the RCT were laryngeal edema, facial attack with laryngeal edema, swelling (shoulder and chest), exacerbation of hereditary angioedema, and laryngospasm. Table 1: Adverse Reactions The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions). Occurring up to 4 hours After Initial Infusion in More Than 4% of Subjects, Irrespective of Causality The following abdominal symptoms were identified in the protocol as associated with HAE abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea. Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions Berinert 20 units/kg (n = 43) Number (%) of Subjects Reporting Adverse Reactions Placebo Group (n = 42) Nausea 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 0 (0) Abdominal Pain 2 (4.7%) 3 (7.1%) Vomiting 1 (2.3%) 3 (7.1%) Diarrhea 0 (0) 4 (9.5%) Headache 0 (0) 2 (4.8%) Table 2: Adverse Reactions The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions). Occurring in More Than 4% of Subjects up to 72 hours After Infusion of Initial or Rescue Medication If a subject experienced no relief or insufficient relief of symptoms within 4 hours after infusion, investigators had the option to administer a blinded second infusion (“rescue” treatment) of Berinert (20 units/kg for the placebo group or 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group). by Intent-to-Treat, Irrespective of Causality Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions Adverse reactions following either initial treatment and/or blinded "rescue" treatment. Because more subjects in the placebo randomization group than in the Berinert randomization group received rescue treatment, the median observation period in this analysis for subjects randomized to placebo was slightly longer than for subjects randomized to receive Berinert. Berinert 20 units/kg (n = 43) Number (%) of Subjects Reporting Adverse Reactions Placebo Group (n = 42) Nausea 3 (7%) 11 (26.2%) Headache 3 (7%) 5 (11.9%) Abdominal Pain 3 (7%) 5 (11.9%) Dysgeusia 2 (4.7%) 1 (2.4%) Vomiting 1 (2.3%) 7 (16.7%) Pain 1 (2.3%) 4 (9.5%) Muscle spasms 1 (2.3%) 4 (9.5%) Diarrhea 0 (0) 8 (19%) Back pain 0 (0) 2 (4.8%) Facial pain 0 (0) 2 (4.8%) Table 3 lists the adverse events that occurred in more than 4% of the subjects 7 to 9 days after the end of a Berinert infusion, irrespective of causality. Table 3: Adverse Events Occurring in More Than 4% of Subjects Includes subjects in the placebo group who received Berinert 20 units/kg as rescue study medication. Receiving Berinert at Either 10 Units/kg or 20 units/kg 7 to 9 Days after Infusion, Irrespective of Causality Adverse Events Number (%) of Subjects Reporting Adverse Events (n=108) Hereditary angioedema 12 (11.1%) Headache 12 (11.1%) Abdominal pain These symptoms were identified in the protocol as related to the underlying disease. Any increase in intensity or new occurrence of these symptoms after study medication administration was considered to be an adverse event. 7 (6.5%) Nausea 7 (6.5%) Muscle spasms 6 (5.6%) Pain 6 (5.6%) Diarrhea 5 (4.6%) Vomiting 5 (4.6%) Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for these pathogens. Extension Study In an interim safety analysis, of the ongoing open-label extension study, 56 subjects with 559 acute moderate to severe abdominal, facial, peripheral, and/or laryngeal attacks received a 20 unit/kg body weight dose of Berinert ( see Clinical Studies [14] ). This study provides additional safety data in subjects who received multiple infusions of the product for sequential HAE attacks (one infusion per attack). Table 4 lists the adverse events that occurred in this interim safety analysis of the ongoing open-label extension study in more than 4% of subjects up to 72 hours or 9 days after the end of a Berinert infusion, irrespective of causality. Table 4: Incidence of Adverse Events by Descending Frequency Occurring in More Than 4% of Subjects Receiving Berinert up to 72 Hours or 9 Days After Infusion, Irrespective of Causality Adverse Events Number (%) of Subjects Reporting Adverse Events up to 72 hours (n=56) Number (%) of Subjects Reporting Adverse Events up to 9 Days (n=56) Headache 3 (5.4%) 4 (7.1%) Abdominal pain 3 (5.4%) 3 (5.4%) Hereditary angioedema 2 (3.6%) 4 (7.1%) Nasopharyngitis 2 (3.6%) 3 (5.4%) 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Adverse reactions reported in Europe since 1979 in patients receiving Berinert for treatment of HAE include hypersensitivity/anaphylactic reactions, a few suspected cases of viral transmission, including cases of acute hepatitis C, injection-site pain, injection-site redness, chills, and fever. The following adverse reactions, identified by system organ class, have been attributed to Berinert during post-approval use outside the US. Immune System Disorder: Hypersensitivity/anaphylactic reactions, and shock General/Body as a Whole: Pain on injection, redness at injection site, chills, and fever

<table width="80%" ID="table1"> <caption>Table 1: Adverse Reactions<footnote ID="t1f1">The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions).</footnote> Occurring up to 4 hours After Initial Infusion in More Than 4% of Subjects, Irrespective of Causality<footnote ID="t1ft2">The following abdominal symptoms were identified in the protocol as associated with HAE abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea.</footnote> </caption> <col width="30%" align="left" valign="top"/> <col width="37%" align="center" valign="top"/> <col width="33%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule" align="center">Adverse Reactions</th> <th styleCode="Rrule">Number (%) of Subjects Reporting Adverse Reactions Berinert 20 units/kg (n = 43)</th> <th styleCode="Rrule">Number (%) of Subjects Reporting Adverse Reactions Placebo Group (n = 42)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea<footnoteRef IDREF="t1ft2"/> </td> <td styleCode="Rrule">3 (7%)</td> <td styleCode="Rrule">5 (11.9%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dysgeusia</td> <td styleCode="Rrule">2 (4.7%)</td> <td styleCode="Rrule">0 (0)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abdominal Pain<footnoteRef IDREF="t1ft2"/> </td> <td styleCode="Rrule">2 (4.7%)</td> <td styleCode="Rrule">3 (7.1%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vomiting<footnoteRef IDREF="t1ft2"/> </td> <td styleCode="Rrule">1 (2.3%)</td> <td styleCode="Rrule">3 (7.1%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea<footnoteRef IDREF="t1ft2"/> </td> <td styleCode="Rrule">0 (0)</td> <td styleCode="Rrule">4 (9.5%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">0 (0)</td> <td styleCode="Rrule">2 (4.8%)</td> </tr> </tbody> </table>

<table width="80%" ID="table2"> <caption>Table 2: Adverse Reactions<footnote ID="t2f1">The study protocol specified that adverse events that began within 72 hours of blinded study medication administration were to be classified as at least possibly related to study medication (ie, adverse reactions).</footnote> Occurring in More Than 4% of Subjects up to 72 hours After Infusion of Initial or Rescue Medication<footnote ID="t2f2">If a subject experienced no relief or insufficient relief of symptoms within 4 hours after infusion, investigators had the option to administer a blinded second infusion (&#x201C;rescue&#x201D; treatment) of Berinert (20 units/kg for the placebo group or 10 units/kg for the 10 units/kg group), or placebo (for the 20 units/kg group).</footnote> by Intent-to-Treat, Irrespective of Causality </caption> <col width="30%" align="left" valign="top"/> <col width="37%" align="center" valign="top"/> <col width="33%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule" align="center">Adverse Reactions</th> <th styleCode="Rrule">Number (%) of Subjects Reporting Adverse Reactions<footnoteRef IDREF="t2f2"/> <footnote ID="t2f3">Adverse reactions following either initial treatment and/or blinded &quot;rescue&quot; treatment. Because more subjects in the placebo randomization group than in the Berinert randomization group received rescue treatment, the median observation period in this analysis for subjects randomized to placebo was slightly longer than for subjects randomized to receive Berinert.</footnote> Berinert 20 units/kg (n = 43)</th> <th styleCode="Rrule">Number (%) of Subjects Reporting Adverse Reactions<footnoteRef IDREF="t2f2"/> <footnoteRef IDREF="t2f3"/> Placebo Group (n = 42)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea</td> <td styleCode="Rrule">3 (7%)</td> <td styleCode="Rrule">11 (26.2%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">3 (7%)</td> <td styleCode="Rrule">5 (11.9%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abdominal Pain</td> <td styleCode="Rrule">3 (7%)</td> <td styleCode="Rrule">5 (11.9%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Dysgeusia</td> <td styleCode="Rrule">2 (4.7%)</td> <td styleCode="Rrule">1 (2.4%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Vomiting</td> <td styleCode="Rrule">1 (2.3%)</td> <td styleCode="Rrule">7 (16.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pain</td> <td styleCode="Rrule">1 (2.3%)</td> <td styleCode="Rrule">4 (9.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Muscle spasms</td> <td styleCode="Rrule">1 (2.3%)</td> <td styleCode="Rrule">4 (9.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea</td> <td styleCode="Rrule">0 (0)</td> <td styleCode="Rrule">8 (19%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Back pain</td> <td styleCode="Rrule">0 (0)</td> <td styleCode="Rrule">2 (4.8%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Facial pain</td> <td styleCode="Rrule">0 (0)</td> <td styleCode="Rrule">2 (4.8%)</td> </tr> </tbody> </table>

<table width="80%" ID="table3"> <col width="50%" align="left" valign="bottom"/> <col width="50%" align="center" valign="bottom"/> <thead> <tr styleCode="Toprule Botrule"> <th colspan="3" align="left" styleCode="Botrule">Table 3: Adverse Events Occurring in More Than 4% of Subjects<footnote ID="t3f1">Includes subjects in the placebo group who received Berinert 20 units/kg as rescue study medication.</footnote> Receiving Berinert at Either 10 Units/kg or 20 units/kg 7 to 9 Days after Infusion, <content styleCode="italics">Irrespective of Causality</content> </th> </tr> <tr> <th styleCode="Lrule Rrule" align="center">Adverse Events</th> <th styleCode="Rrule">Number (%) of Subjects Reporting Adverse Events (n=108)</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Hereditary angioedema</td> <td styleCode="Rrule">12 (11.1%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">12 (11.1%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Abdominal pain<footnote ID="t3ft2">These symptoms were identified in the protocol as related to the underlying disease. Any increase in intensity or new occurrence of these symptoms after study medication administration was considered to be an adverse event.</footnote> </td> <td styleCode="Rrule">7 (6.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Nausea<footnoteRef IDREF="t3ft2"/> </td> <td styleCode="Rrule">7 (6.5%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Muscle spasms</td> <td styleCode="Rrule">6 (5.6%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pain</td> <td styleCode="Rrule">6 (5.6%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Diarrhea<footnoteRef IDREF="t3ft2"/> </td> <td styleCode="Rrule">5 (4.6%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Vomiting<footnoteRef IDREF="t3ft2"/> </td> <td styleCode="Rrule">5 (4.6%)</td> </tr> </tbody> </table>