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Description for Kloxxado

KLOXXADO (naloxone hydrochloride) nasal spray is an opioid antagonist supplied in a pre-filled intranasal device designed to deliver a single dose of 8 mg of naloxone hydrochloride (equivalent to 7.2 mg naloxone) in 0.1mL.

Chemically, naloxone hydrochloride is the hydrochloride salt of 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride with molecular weight of 363.84 g/mol.

Its molecular formula is C19H21NO4.HCl, and it has the following chemical structure, as shown below.

Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.

The inactive ingredients in KLOXXADO nasal spray include: dehydrated alcohol (20% (w/w)) edetate disodium dihydrate, propylene glycol, purified water, and sodium hydroxide and hydrochloric acid to adjust pH. The pH range is from 4.0 to 5.5.

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)]

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.

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 postapproval use of naloxone hydrochloride (all routes of administration): withdrawal syndrome, vomiting, nonresponsiveness to stimuli, drug ineffective, agitation, somnolence, and loss of consciousness.

Drug Interactions for Kloxxado

No information provided

Warnings for Kloxxado

Included as part of the PRECAUTIONS section.

Precautions for Kloxxado

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.

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.

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)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Studies in animals to assess the carcinogenic potential of naloxone have not been conducted.

Mutagenesis

Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.

Impairment of Fertility

Reproduction studies conducted in mice and rats at doses 3-times and 6-times, respectively, a human dose of 16 mg based on body surface area comparison, demonstrated no adverse effects on fertility of naloxone hydrochloride.

Patient Information for Kloxxado

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).  

Recognition of Opioid Overdose

Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following:

• Extreme somnolence – inability to awaken a patient verbally or upon a firm sternal rub.
• Respiratory depression – this can range from slow or shallow respiration to no respiration in a patient who is unarousable.
• Other signs and symptoms that may accompany somnolence and respiratory depression include the following:
• Miosis
• Bradycardia and/or hypotension

Risk of Recurrent Respiratory and Central Nervous System Depression

Instruct patients and their family members or caregivers that, because the duration of action of most opioids may exceed that of KLOXXADO, they must seek immediate emergency medical assistance after the first dose of KLOXXADO and keep the patient under continued surveillance [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of KLOXXADO, using a new nasal spray each time [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Precipitation of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of KLOXXADO in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions (5.3), Adverse Reactions (6)].

Administration Instructions

Instruct patients and their family members or caregivers to:

• Ensure KLOXXADO is present and readily available in locations where a person may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).
• Administer KLOXXADO as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. KLOXXADO is not a substitute for emergency medical care [see Dosage and Administration (2.1)].
• Lay the patient on their back and administer KLOXXADO into one nostril while providing support to the back of the neck to allow the head to tilt back [see Dosage and Administration (2.1)].
• Use each nasal spray only one time, DO NOT test or prime prior to use[see Dosage and Administration (2.1)].
• Place patient in a recovery position by turning him/her to their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of KLOXXADO. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)].
• Monitor patients and administer additional dose of KLOXXADO using a new KLOXXADO every 2 to 3 minutes, if the patient is not responding or responds and then relapses back into respiratory depression. Administer KLOXXADO in alternate nostrils with each dose [see Dosage and Administration (2.1)].
• Replace KLOXXADO before its expiration date.

Distributed by: Hikma Specialty USA Inc. Columbus, OH 43228 C50001184/01 Revised AUGUST 2025 KLOXXADO® is a registered trademark of Hikma Pharmaceuticals USA Inc.

OVERDOSAGE

No information provided

Contraindications for Kloxxado

KLOXXADO is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients in KLOXXADO.

Clinical Pharmacology for Kloxxado

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.

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.

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)

Table 1: Mean (CV%) Plasma Pharmacokinetic Parameters of Naloxone Following a Single Dose of 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	711	702	702
Tmax(h)3	0.17 (0.07-0.50)	0.25 (0.13-1.00)	0.25 (0.07-1.00)
Cmax (ng/mL)	11.11 (41.74)	6.56 (35.87)	14.41 (47.17)
AUClast (ng¡h/mL)	12.31 (31.61)	10.14 (35.44)	19.57 (35.39)
AUC0àinf (ng¡h/mL)	12.57 (30.63)	10.41 (33.82)	19.81 (34.73)
T1/2 (h)	1.27 (26.32)	1.30 (26.22)	1.56 (126.82)
N=71 due to withdrawal. N=70 due to withdrawal. Tmax reported as median (minimum maximum).

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	231	24	231	24
Tmax(h)2	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
Cmax (ng/mL)	12.3 (55.4)	12.8 (37.0)	0.876 (36.7)	0.910 (36.8)	26.2 (82.4)3
AUClast   (ng•h/mL)	18.0 (29.6)	18.4 (33.4)	1.82 (24.0)	1.87 (24.7)	12.7 (27.6)
AUC0- inf(ng•h/mL)	16.7 (31.9)4	19.0 (32.7)5	1.94 (20.9)6	1.95 (21.9)	12.8 (27.5)
t1/2 (h)	2.69 (69.9)	1.76 (39.7)5	1.41 (20.0)6	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 N=23 due to one subject withdrawal. Tmax reported as median (minimum maximum). Cmax of Intravenous Injection 2 mg was observed value from the first sampling time of 2 minutes post-dose. N=15 N=19 N=22 for AUC0-inf and t1/2

The median Tmax 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 8mg were 0.17 hour, 0.25 hour, and 0.25 hour, respectively. The median Tmax (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 (t1/2) of naloxone in plasma was approximately 1.27 (26.32% CV) hours. The mean t1/2 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 (t1/2) of naloxone in plasma was 1.8 (39.7% CV) to 2.7 (69.6% CV) hours. The mean t1/2 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.

You and your family members or caregivers should read the Instructions for Use that comes with KLOXXADO nasal spray before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of KLOXXADO nasal spray.

Use KLOXXADO nasal spray for known or suspected opioid overdose in adults and children.

Important: For use in the nose only.

• Do not remove or test the KLOXXADO nasal spray until ready to use.
• Each KLOXXADO nasal spray has 1 dose and cannot be reused.
• You do not need to prime KLOXXADO nasal spray.

How to use KLOXXADO nasal spray: Step 1. Lay the person on their back to receive a dose of KLOXXADO nasal spray. Step 2. Remove KLOXXADO nasal spray from the box. Peel back the tab with the black triangle (?) to open the KLOXXADO nasal spray blister. Note: KLOXXADO freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. Get emergency medical help right away if this happens. Do not wait for KLOXXADO to thaw. KLOXXADO may still be used if it has been thawed after being previously frozen.
Step 3. Hold the KLOXXADO nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle. Do not apply any pressure until you are ready to give the dose.
Step 4. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person’s nose.
Step 5. Press the plunger firmly to give the dose of KLOXXADO nasal spray. Step 6. Remove the KLOXXADO nasal spray from the nostril after giving the dose.
What to do after KLOXXADO nasal spray has been used: Step 7. Get emergency help right away. Move the person on their side (recovery position) after giving KLOXXADO nasal spray. Watch the person closely for 2 to 3 minutes. If the person does not respond by waking up, to voice or touch, or start breathing normally, another dose may be given. Repeat Steps 2 through 6 using a new KLOXXADO nasal spray to give another dose in the other nostril. If additional KLOXXADO nasal sprays are available, Steps 2 through 6 may be repeated every 2 to 3 minutes, alternating nostrils, until the person responds or emergency medical help is received.
Step 8. Put the used KLOXXADO nasal spray back into its box. Step 9. Throw away (dispose of) the used KLOXXADO nasal spray in a place that is away from children.
How should I store KLOXXADO nasal spray? Store KLOXXADO nasal spray at room temperature between 68ºF to 77ºF (20°C to 25°C). Do not freeze. Do not expose to temperatures below 41°F (5°C) or above 104°F (40°C). Keep KLOXXADO nasal spray in its box until ready to use. Protect from light. Replace KLOXXADO nasal spray before the expiration date on the box. Keep KLOXXADO nasal spray and all medicines out of the reach of children. Distributed by: Hikma Specialty USA Inc., Columbus, OH 43228 C50001184/01 KLOXXADO® is a registered trademark of Hikma Pharmaceuticals USA Inc. For more information, visit www.Hikma.com or call Hikma Specialty USA Inc. at 1-800-962-8364. This Instructions for Use has been approved by the U.S. Food and Drug Administration.