Naloxone Hcl

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 )].

8.1 Pregnancy Risk Summary Available data from retrospective cohort studies on naloxone use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Naloxone may precipitate opioid withdrawal in the pregnant woman and fetus [see Warnings and Precautions ( 5.3 ) and Clinical Considerations ] . In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 3-times and 6-times, respectively, a human dose of 16 mg (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population(s) 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 Maternal and Fetal/Neonatal Adverse Reactions Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother [see Warnings and Precautions ( 5.3 )] . The fetus should be evaluated for signs of distress after KLOXXADO is used. Careful monitoring is needed until the fetus and mother are stabilized. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 3-times and 6-times, respectively, a human dose of 16 mg based on body surface area comparison. These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

8.2 Lactation Risk Summary There is no information regarding the presence of naloxone in human milk, the effects of naloxone on the breastfed infant or on milk production. Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally available and is unlikely to affect the breastfed infant.

8.4 Pediatric Use The safety and effectiveness of KLOXXADO have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in pediatric patients is supported by evidence from adult bioavailability studies with additional evidence from the reported safe and effective use of other naloxone hydrochloride products. No pediatric studies were conducted for KLOXXADO. Absorption of naloxone hydrochloride following intranasal administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours, as a relapse may occur as naloxone hydrochloride is metabolized. In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. 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. Unlike acute opioid withdrawal in adults, acute opioid withdrawal in neonates manifesting as seizures may be life-threatening if not recognized and properly treated. Other signs and symptoms in neonates may include excessive crying and hyperactive reflexes. In these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative, naloxone hydrochloride product that can be dosed according to weight and titrated to effect [see Warnings and Precautions ( 5.3 )]. Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availability of alternate naloxone-containing products may be better suited than KLOXXADO. Juvenile Animal Study In a juvenile animal study, male and female juvenile rats were administered a single intranasal dose of saline, vehicle consisting of 20% alcohol and 5% propylene glycol, or naloxone (123 mg/kg, 185 mg/kg, and 246 mg/kg) on postnatal day 7 (PND 7). There were no test article-related findings on sexual maturation, neuroapoptosis, or on a limited number of neurocognitive endpoints which included social interactions as well as learning and memory. The no-effect dose level for neurodevelopmental toxicity was the high dose tested, which is 2.7-times a neonate dose based on body surface area comparison and a neonate weight of 2.5 kg.

8.5 Geriatric Use Clinical studies of KLOXXADO 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.

12.1 Mechanism of Action Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. Administration of naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2 Pharmacodynamics When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

12.3 Pharmacokinetics In a pharmacokinetic study in up to 72 healthy adult volunteers under fasting conditions, the bioavailability (BA) of a single 4 mg dose (one spray) of KLOXXADO was compared to a single 8 mg nasal dose of KLOXXADO and a single 4 mg nasal dose of a previously approved naloxone nasal spray. Naloxone plasma concentration versus time profiles are shown in Figure 1. The pharmacokinetic parameters of naloxone are summarized in Table 1. Figure 1. Mean ± SD Plasma Concentration Time Profiles of Naloxone Following a Single Dose of Kloxxado nasal spray 4 mg versus Kloxxado 8 mg nasal spray, and a Previously Approved naloxone nasal spray 4 mg in Healthy Subjects (A: 0-4h and B: 0-30 min) Kloxxado nasal spray 4 mg, Kloxxado nasal spray 8 mg, and a Previously Approved Naloxone Nasal Spray 4 mg Administration in Healthy Subjects Kloxxado nasal spray 4 mg, Kloxxado nasal spray 8 mg, and a Previously Approved Naloxone Nasal Spray 4 mg Administration in Healthy Subjects Parameter Kloxxado Nasal Spray 4 mg Previously Approved Naloxone Nasal Spray 4 mg Kloxxado Nasal Spray 8 mg N 71 N=71 due to withdrawal. 70 N=70 due to withdrawal. 70 T max (h) T max reported as median (minimum – maximum). 0.17 (0.07-0.50) 0.25 (0.13-1.00) 0.25 (0.07-1.00) C max (ng/mL) 11.11 (41.74) 6.56 (35.87) 14.41 (47.17) AUC last (ngh/mL) 12.31 (31.61) 10.14 (35.44) 19.57 (35.39) AUC 0inf (ngh/mL) 12.57 (30.63) 10.41 (33.82) 19.81 (34.73) T 1/2 (h) 1.27 (26.32) 1.30 (26.22) 1.56 (126.82) In two pharmacokinetic studies in up to 24 healthy adult volunteers for each study, the bioavailability (BA) of a single 8 mg dose (one spray) of KLOXXADO was compared to a single 0.4 mg intramuscular dose and a single 2 mg intravenous dose of naloxone. Naloxone plasma concentration versus time profiles are shown in Figure 2. The pharmacokinetic parameters of naloxone are summarized in Table 2. Figure 2. Mean ± SD Plasma Concentration-Time Profiles of Naloxone Following A Single Dose of Intranasal versus Intramuscular/Intravenous Administration in Healthy Subjects. (A: 0-4 h and B: 0-30 min.) Table 2. Mean (CV%) Plasma Pharmacokinetic Parameters of Naloxone Following a Single Dose of Intranasal and Intramuscular/Intravenous Administration in Healthy Subjects Parameter KLOXXADO 8 mg Intramuscular Injection 0.4 mg Intravenous Injection 2 mg Study Study I Study II Study I Study II Study II N 24 23 N=23 due to one subject withdrawal. 24 23 24 T max (h) T max reported as median (minimum – maximum). 0.25 (0.10 – 1.00) 0.25 (0.10 – 1.00) 0.25 (0.13 – 1.00) 0.25 (0.10 – 1.00) NA C max (ng/mL) 12.3 (55.4) 12.8 (37.0) 0.876 (36.7) 0.910 (36.8) 26.2 (82.4) C max of Intravenous Injection 2 mg was observed value from the first sampling time of 2 minutes post-dose. AUC last (ng

• h/mL) 18.0 (29.6) 18.4 (33.4) 1.82 (24.0) 1.87 (24.7) 12.7 (27.6) AUC 0-inf (ng
• h/mL) 16.7 (31.9) N=15 19.0 (32.7) N=19 1.94 (20.9) N=22 for AUC 0-inf and t 1/2 1.95 (21.9) 12.8 (27.5) t 1/2 (h) 2.69 (69.9) 1.76 (39.7) 1.41 (20.0) 1.40 (38.9) 1.22 (16.4) Dose normalized Relative BA (%) vs IM Injection 41.6 47.4 100 100 NA Dose normalized Absolute BA (%) vs IV Injection NA 36.6 NA 77.2 100 NA= Not applicable Absorption The median T max for naloxone following administration of a single dose of 4 mg Kloxxado nasal spray, a previously approved naloxone nasal spray 4 mg, and Kloxxado nasal spray 8 mg were 0.17 hour, 0.25 hour, and 0.25 hour, respectively. The median T max (15 min) for naloxone following administration of a single dose of 8 mg KLOXXADO nasal spray was the same as following administration of a single intramuscular dose of 0.4 mg naloxone hydrochloride. The relative bioavailability of naloxone following administration of a single dose 4 mg Kloxxado nasal spray was 122% as compared to following administration of a single intranasal dose of a previously approved naloxone nasal spray 4 mg. The relative bioavailability of naloxone following administration of a single dose of 4 mg Kloxxado nasal spray was 65% as compared to following administration of a single intranasal dose of 8 mg Kloxxado. The dose normalized relative bioavailability of naloxone following administration of a single dose of 8 mg KLOXXADO was 42 to 47% as compared to following administration of a single intramuscular dose of 0.4 mg naloxone hydrochloride. The absolute bioavailability of naloxone following administration of a single dose of 8 mg KLOXXADO nasal spray was 37% as compared to following administration of a single intravenous dose of 2 mg naloxone hydrochloride. Distribution Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constitute, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Elimination Following a single intranasal administration of Kloxxado nasal spray 4 mg, the mean half-life (t 1/2 ) of naloxone in plasma was approximately 1.27 (26.32% CV) hours. The mean t 1/2 was 1.30 (26.22% CV) hours for a 4 mg intranasal administration of a previously approved naloxone nasal spray and 1.56 (126.82% CV) hours for an 8 mg Kloxxado intranasal administration. Following a single intranasal administration of 8 mg KLOXXADO, the mean half-life (t 1/2 ) of naloxone in plasma was 1.8 (39.7% CV) to 2.7 (69.6% CV) hours. The mean t 1/2 was 1.4 (38.9% CV) to 1.4 (20.0% CV) hours for a 0.4 mg naloxone hydrochloride intramuscular injection and 1.2 (16.4% CV) hours for a 2 mg naloxone hydrochloride intravenous injection. In a neonatal study of naloxone hydrochloride the mean (±SD) plasma half-life was observed to be 3.1 ± 0.5 hours. Metabolism Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite. Excretion After an oral or intravenous dose, about 25 to 40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours. figure1-plot-a-09.29.2025.jpg figure1-plot-b-09.29.2025.jpg figure-2-plot-a-09.29.2025.jpg figure-2-plot-b-09.29.2025.jpg

In a pharmacokinetic study in up to 72 healthy adult volunteers under fasting conditions, the bioavailability (BA) of a single 4 mg dose (one spray) of KLOXXADO was compared to a single 8 mg nasal dose of KLOXXADO and a single 4 mg nasal dose of a previously approved naloxone nasal spray. Naloxone plasma concentration versus time profiles are shown in Figure 1. The pharmacokinetic parameters of naloxone are summarized in Table 1. Figure 1. Mean ± SD Plasma Concentration Time Profiles of Naloxone Following a Single Dose of Kloxxado nasal spray 4 mg versus Kloxxado 8 mg nasal spray, and a Previously Approved naloxone nasal spray 4 mg in Healthy Subjects (A: 0-4h and B: 0-30 min) Kloxxado nasal spray 4 mg, Kloxxado nasal spray 8 mg, and a Previously Approved Naloxone Nasal Spray 4 mg Administration in Healthy Subjects Kloxxado nasal spray 4 mg, Kloxxado nasal spray 8 mg, and a Previously Approved Naloxone Nasal Spray 4 mg Administration in Healthy Subjects Parameter Kloxxado Nasal Spray 4 mg Previously Approved Naloxone Nasal Spray 4 mg Kloxxado Nasal Spray 8 mg N 71 N=71 due to withdrawal. 70 N=70 due to withdrawal. 70 T max (h) T max reported as median (minimum – maximum). 0.17 (0.07-0.50) 0.25 (0.13-1.00) 0.25 (0.07-1.00) C max (ng/mL) 11.11 (41.74) 6.56 (35.87) 14.41 (47.17) AUC last (ngh/mL) 12.31 (31.61) 10.14 (35.44) 19.57 (35.39) AUC 0inf (ngh/mL) 12.57 (30.63) 10.41 (33.82) 19.81 (34.73) T 1/2 (h) 1.27 (26.32) 1.30 (26.22) 1.56 (126.82) In two pharmacokinetic studies in up to 24 healthy adult volunteers for each study, the bioavailability (BA) of a single 8 mg dose (one spray) of KLOXXADO was compared to a single 0.4 mg intramuscular dose and a single 2 mg intravenous dose of naloxone. Naloxone plasma concentration versus time profiles are shown in Figure 2. The pharmacokinetic parameters of naloxone are summarized in Table 2. Figure 2. Mean ± SD Plasma Concentration-Time Profiles of Naloxone Following A Single Dose of Intranasal versus Intramuscular/Intravenous Administration in Healthy Subjects. (A: 0-4 h and B: 0-30 min.) Table 2. Mean (CV%) Plasma Pharmacokinetic Parameters of Naloxone Following a Single Dose of Intranasal and Intramuscular/Intravenous Administration in Healthy Subjects Parameter KLOXXADO 8 mg Intramuscular Injection 0.4 mg Intravenous Injection 2 mg Study Study I Study II Study I Study II Study II N 24 23 N=23 due to one subject withdrawal. 24 23 24 T max (h) T max reported as median (minimum – maximum). 0.25 (0.10 – 1.00) 0.25 (0.10 – 1.00) 0.25 (0.13 – 1.00) 0.25 (0.10 – 1.00) NA C max (ng/mL) 12.3 (55.4) 12.8 (37.0) 0.876 (36.7) 0.910 (36.8) 26.2 (82.4) C max of Intravenous Injection 2 mg was observed value from the first sampling time of 2 minutes post-dose. AUC last (ng

• h/mL) 18.0 (29.6) 18.4 (33.4) 1.82 (24.0) 1.87 (24.7) 12.7 (27.6) AUC 0-inf (ng
• h/mL) 16.7 (31.9) N=15 19.0 (32.7) N=19 1.94 (20.9) N=22 for AUC 0-inf and t 1/2 1.95 (21.9) 12.8 (27.5) t 1/2 (h) 2.69 (69.9) 1.76 (39.7) 1.41 (20.0) 1.40 (38.9) 1.22 (16.4) Dose normalized Relative BA (%) vs IM Injection 41.6 47.4 100 100 NA Dose normalized Absolute BA (%) vs IV Injection NA 36.6 NA 77.2 100 NA= Not applicable Absorption The median T max for naloxone following administration of a single dose of 4 mg Kloxxado nasal spray, a previously approved naloxone nasal spray 4 mg, and Kloxxado nasal spray 8 mg were 0.17 hour, 0.25 hour, and 0.25 hour, respectively. The median T max (15 min) for naloxone following administration of a single dose of 8 mg KLOXXADO nasal spray was the same as following administration of a single intramuscular dose of 0.4 mg naloxone hydrochloride. The relative bioavailability of naloxone following administration of a single dose 4 mg Kloxxado nasal spray was 122% as compared to following administration of a single intranasal dose of a previously approved naloxone nasal spray 4 mg. The relative bioavailability of naloxone following administration of a single dose of 4 mg Kloxxado nasal spray was 65% as compared to following administration of a single intranasal dose of 8 mg Kloxxado. The dose normalized relative bioavailability of naloxone following administration of a single dose of 8 mg KLOXXADO was 42 to 47% as compared to following administration of a single intramuscular dose of 0.4 mg naloxone hydrochloride. The absolute bioavailability of naloxone following administration of a single dose of 8 mg KLOXXADO nasal spray was 37% as compared to following administration of a single intravenous dose of 2 mg naloxone hydrochloride. Distribution Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constitute, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Elimination Following a single intranasal administration of Kloxxado nasal spray 4 mg, the mean half-life (t 1/2 ) of naloxone in plasma was approximately 1.27 (26.32% CV) hours. The mean t 1/2 was 1.30 (26.22% CV) hours for a 4 mg intranasal administration of a previously approved naloxone nasal spray and 1.56 (126.82% CV) hours for an 8 mg Kloxxado intranasal administration. Following a single intranasal administration of 8 mg KLOXXADO, the mean half-life (t 1/2 ) of naloxone in plasma was 1.8 (39.7% CV) to 2.7 (69.6% CV) hours. The mean t 1/2 was 1.4 (38.9% CV) to 1.4 (20.0% CV) hours for a 0.4 mg naloxone hydrochloride intramuscular injection and 1.2 (16.4% CV) hours for a 2 mg naloxone hydrochloride intravenous injection. In a neonatal study of naloxone hydrochloride the mean (±SD) plasma half-life was observed to be 3.1 ± 0.5 hours. Metabolism Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite. Excretion After an oral or intravenous dose, about 25 to 40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours. figure1-plot-a-09.29.2025.jpg figure1-plot-b-09.29.2025.jpg figure-2-plot-a-09.29.2025.jpg figure-2-plot-b-09.29.2025.jpg