KLOXXADO

5 WARNINGS AND PRECAUTIONS • Risk of Recurrent Respiratory and CNS Depression : Due to the duration of action of naloxone relative to the opioid, keep patient under continued surveillance and administer repeat doses of naloxone using a new nasal spray with each dose, as necessary, while awaiting emergency medical assistance. ( 5.1 ) • Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists : Reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be necessary. ( 5.2 ) • Precipitation of Severe Opioid Withdrawal : Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. ( 5.3 ) • Risk of Cardiovascular (CV) Effects : Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had preexisting CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of naloxone hydrochloride. ( 5.3 ) 5.1 Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of KLOXXADO resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency assistance immediately after administration of the first dose of KLOXXADO and to keep the patient under continued surveillance. Administer additional doses of KLOXXADO if the patient is not adequately responding or responds and then relapses back into respiratory depression, as necessary [see Dosage and Administration ( 2.2 )] . Additional supportive and/or resuscitative measure may be helpful while awaiting emergency medical assistance. 5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists Reversal of respiratory depression by partial agonists or mixed/antagonists such as buprenorphine and pentazocine may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration ( 2.2 )] . Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. 5.3 Precipitation of Severe Opioid Withdrawal The use of KLOXXADO in patients who are opioid-dependent may precipitate opioid withdrawal; the risk and severity of withdrawal increases as naloxone exposure increases. Opioid withdrawal is characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsion, excessive crying, and hyperactive reflexes. Monitor the patient for the development of the signs and symptoms of opioid withdrawal. Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. Monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone-containing product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Population ( 8.4 )].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions ( 5.1 )] • Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions ( 5.3 )] The following adverse reactions were reported with KLOXXADO in two adult subjects each: abdominal pain, asthenia, dizziness, headache, nasal discomfort, and presyncope. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Specialty USA Inc. at 1-800-962-8364 or 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 studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. KLOXXADO nasal spray, 4 mg No adverse events were reported in a pharmacokinetic study of 72 healthy adult volunteers exposed to one spray of 4 mg KLOXXADO nasal spray in one nostril. KLOXXADO nasal spray, 8 mg In two pharmacokinetic studies a total of 47 healthy adult volunteers were exposed to a single dose of KLOXXADO nasal spray 8 mg, one spray in one nostril. The following adverse reactions were reported in two subjects each: abdominal pain, asthenia, dizziness, headache, nasal discomfort, and presyncope. On local tissue assessments for nasal irritation, signs of nasal inflammation and nasal congestion were observed. 6.2 Postmarketing Experience The following adverse events have been identified during the post-approval use of naloxone hydrochloride injection in the postoperative setting. 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: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone hydrochloride in postoperative patients have resulted in significant reversal of analgesia and have caused agitation. Abrupt reversal of opioid effects in persons who were physically dependent on opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In some patients, there was aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal has included: convulsions, excessive crying, hyperactive reflexes [see Warnings and Precautions ( 5.3 )] . The following most frequently reported events (in decreasing frequency) have been identified primarily during post-approval use of naloxone hydrochloride (all routes of administration): withdrawal syndrome, vomiting, nonresponsiveness to stimuli, drug ineffective, agitation, somnolence, and loss of consciousness.