Ibuprofen Lysine

5 WARNINGS AND PRECAUTIONS Ibuprofen Lysine has not been assessed for neurodevelopmental outcome and growth (5.1) Ibuprofen Lysine may alter the usual signs of infection (5.2) Ibuprofen Lysine can inhibit platelet aggregation, and has been shown to prolong bleeding time in normal adult subjects (5.3) Ibuprofen has been shown to displace bilirubin from albumin binding-sites (5.4) Ibuprofen Lysine should be administered carefully to avoid extravascular injection or leakage (5.5) Ibuprofen Lysine may cause serious skin reactions ( 5.6 ) 5.1 General There are no long-term evaluations of the infants treated with ibuprofen at durations greater than the 36 weeks post-conceptual age observation period. Ibuprofen's effects on neurodevelopmental outcome and growth as well as disease processes associated with prematurity (such as retinopathy of prematurity and chronic lung disease) have not been assessed. 5.2 Infection Ibuprofen Lysine may alter the usual signs of infection. The physician must be continually on the alert and should use the drug with extra care in the presence of controlled infection and in infants at risk of infection. 5.3 Platelet Aggregation Ibuprofen Lysine, like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation. Preterm infants should be observed for signs of bleeding. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. This effect may be exaggerated in patients with underlying hemostatic defects (see CONTRAINDICATIONS ). 5.4 Bilirubin Displacement Ibuprofen has been shown to displace bilirubin from albumin binding-sites; therefore, it should be used with caution in patients with elevated total bilirubin. 5.5 Administration Ibuprofen Lysine should be administered carefully to avoid extravascular injection or leakage, as solution may be irritating to tissue. 5.6 Serious Skin Reactions NSAIDS, including ibuprofen, can cause serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), which can be fatal. Ibuprofen should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

6 ADVERSE REACTIONS Most common adverse reactions (≥10%) are sepsis, anemia, intraventricular bleeding, apnea, gastrointestinal disorders, impaired renal function, respiratory infection, skin lesions, hypoglycemia, hypocalcemia, respiratory failure. (6) To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The most frequently reported adverse events with Ibuprofen Lysine were as shown in Table 1. Table 1. Adverse Events within 30 Days of Therapy in the Multicenter Study Within 30 days of therapy, with an event rate greater on Ibuprofen Lysine than on placebo, and greater than 2 events on Ibuprofen Lysine. % Incidence Adverse Event Ibuprofen Lysine Placebo Sepsis 43 37 Anemia 32 25 Total Bleeding A given subject may have experienced more than one specific event within these adverse event categories. Only the most severe grade of IVH counted for a given subject. 32 29 Intraventricular Hemorrhage, Grades 1/2 15 13 Intraventricular Hemorrhage, Grades 3/4 15 10 Other Bleeding 6 13 Intraventricular Hemorrhage, All Grades 29 24 Apnea 28 26 Gastrointestinal Disorders 22 18 non-Necrotizing Enterocolitis Total Renal Events 21 15 Renal Failure 1 3 Renal Insufficiency, Impairment 6 4 Urine Output Reduced 3 1 Blood Creatinine Increased 3 1 Blood Urea Increased with Hematuria 1 1 Blood Urea Increased 7 4 Respiratory Infection 19 13 Skin Lesion/Irritation 16 6 Hypoglycemia 12 6 Hypocalcemia 12 9 Respiratory Failure 10 4 Urinary Tract Infection 9 4 Adrenal Insufficiency 7 1 Hypernatremia 7 4 Edema 4 0 Atelectasis 4 1 6.2 Renal Function Compared to placebo, there was a small decrease in urinary output in the ibuprofen group on days 2-6 of life, with a compensatory increase in urine output on day 9. In other studies, adverse events classified as renal insufficiency including oliguria, elevated BUN, elevated creatinine, or renal failure were reported in ibuprofen treated infants. 6.3 Additional Adverse Events The adverse events reported in the multicenter study and of unknown association include tachycardia, cardiac failure, abdominal distension, gastroesophageal reflux, gastritis, ileus, inguinal hernia, injection site reactions, cholestasis, various infections, feeding problems, convulsions, jaundice, hypotension, and various laboratory abnormalities including neutropenia, thrombocytopenia, and hyperglycemia. 6.4 Post-marketing Experience 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 have been identified from spontaneous post-marketing reports or published literature: gastrointestinal perforation, necrotizing enterocolitis, drug reaction with eosinophilia and systemic symptoms (DRESS), and pulmonary hypertension.

<table width="60%"><caption>Table 1. Adverse Events within 30 Days of Therapy in the Multicenter Study<footnote ID="t1ft1">Within 30 days of therapy, with an event rate greater on Ibuprofen Lysine than on placebo, and greater than 2 events on Ibuprofen Lysine.</footnote></caption><col width="56%" align="left" valign="top"/><col width="22%" align="center" valign="top"/><col width="22%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule" colspan="2">% Incidence</th></tr><tr><th styleCode="Lrule Rrule">Adverse Event</th><th align="center">Ibuprofen Lysine</th><th styleCode="Rrule" align="center">Placebo</th></tr></thead><tbody><tr><td styleCode="Lrule">Sepsis</td><td align="left">43</td><td styleCode="Rrule">37</td></tr><tr><td styleCode="Lrule">Anemia</td><td align="left">32</td><td styleCode="Rrule">25</td></tr><tr><td styleCode="Lrule">Total Bleeding<footnote ID="t1ft2">A given subject may have experienced more than one specific event within these adverse event categories. Only the most severe grade of IVH counted for a given subject.</footnote></td><td align="left">32</td><td styleCode="Rrule">29</td></tr><tr><td styleCode="Lrule"> Intraventricular Hemorrhage, Grades 1/2</td><td align="left">15</td><td styleCode="Rrule" valign="bottom">13</td></tr><tr><td styleCode="Lrule"> Intraventricular Hemorrhage, Grades 3/4</td><td align="left">15</td><td styleCode="Rrule" valign="bottom">10</td></tr><tr><td styleCode="Lrule"> Other Bleeding</td><td align="left">6</td><td styleCode="Rrule">13</td></tr><tr><td styleCode="Lrule">Intraventricular Hemorrhage, All Grades</td><td align="left">29</td><td styleCode="Rrule" valign="bottom">24</td></tr><tr><td styleCode="Lrule">Apnea</td><td align="left">28</td><td styleCode="Rrule">26</td></tr><tr><td styleCode="Lrule">Gastrointestinal Disorders</td><td align="left">22</td><td styleCode="Rrule">18</td></tr><tr><td styleCode="Lrule"> non-Necrotizing Enterocolitis</td><td/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule">Total Renal Events<footnoteRef IDREF="t1ft2"/></td><td align="left">21</td><td styleCode="Rrule">15</td></tr><tr><td styleCode="Lrule"> Renal Failure</td><td align="left">1</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule"> Renal Insufficiency, Impairment</td><td align="left">6</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule"> Urine Output Reduced</td><td align="left">3</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule"> Blood Creatinine Increased</td><td align="left">3</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule"> Blood Urea Increased with Hematuria</td><td align="left">1</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule"> Blood Urea Increased</td><td align="left">7</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule">Respiratory Infection</td><td align="left">19</td><td styleCode="Rrule">13</td></tr><tr><td styleCode="Lrule">Skin Lesion/Irritation</td><td align="left">16</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule">Hypoglycemia</td><td align="left">12</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule">Hypocalcemia</td><td align="left">12</td><td styleCode="Rrule">9</td></tr><tr><td styleCode="Lrule">Respiratory Failure</td><td align="left">10</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule">Urinary Tract Infection</td><td align="left">9</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule">Adrenal Insufficiency</td><td align="left">7</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule">Hypernatremia</td><td align="left">7</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule">Edema</td><td align="left">4</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule">Atelectasis</td><td align="left">4</td><td styleCode="Rrule">1</td></tr></tbody></table>