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Naloxone hydrochloride is an opioid antagonist. It is chemically identified as 17-allyl-4,5α-epoxy-3,14-dihydroxy morphinan-6-one hydrochloride dihydrate. Its molecular formula is C19H21NO4• HCl•2H2O and has a molecular weight of 399.87 g/mol. It has the following structural formula:
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Naloxone hydrochloride dihydrate occurs as a white to slightly off-white powder. It is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.
REXTOVY Nasal Spray is a prefilled unit-dose intranasal spray. Naloxone hydrochloride is contained as a solution in a stoppered glass vial within the nasal spray device. Each REXTOVY device delivers a single spray containing 4 mg of naloxone hydrochloride (equivalent to 3.6 mg of naloxone) in 0.25 mL of aqueous solution with a pH of 3.5 to 5.0.
Inactive ingredients include sodium chloride, sodium hydroxide to adjust pH, and water for injection USP.
REXTOVY Nasal Spray is indicated for emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression, for adult and pediatric patients.
REXTOVY Nasal Spray is intended for immediate administration as emergency therapy in settings where opioids may be present.
REXTOVY Nasal Spray is not a substitute for emergency medical care.
Important Administration Instructions
Figure 1 : REXTOVY Nasal Spray Device
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The recommended initial dose of REXTOVY Nasal Spray in adults and pediatric patients is one spray delivered by intranasal administration, which delivers 4 mg of naloxone hydrochloride.
Seek emergency medical assistance as soon as possible after administering the REXTOVY Nasal Spray. The reÂquirement for repeat doses of REXTOVY Nasal Spray depends upon the amount, type, and route of administration of the opioid being antagonized.
Administer REXTOVY Nasal Spray in alternate nostrils with each dose.
If the patient responds to REXTOVY Nasal Spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of REXTOVY Nasal Spray in opposite nostril using a new REXÂTOVY Nasal Spray device and continue surveillance of the patient.
If the desired response is not obtained after 2 minutes, administer an additional dose of REXTOVYNasal Spray using a new REXTOVY Nasal Spray device. If there is still no response and additional doses are available, administer additional doses of REXTOVY Nasal Spray every 2 to 3 minutes using a new REXTOVY Nasal Spray device with each dose until emergency medical assistance arrives.
Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.
Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazÂocine, may be incomplete and require higher doses of naloxone hydrochloride or repeated administration of REXTOVY Nasal Spray using a new REXTOVY Nasal Spray [see WARNINGS AND PRECAUTIONS].
Nasal spray: 4 mg of naloxone hydrochloride per device. Each unit-dose REXTOVY nasal spray device delivers a single spray containing 4 mg of naloxone hydrochloride.
Each carton contains two unit-dose REXTOVY Nasal Spray devices. Each device delivers a single spray containing 4 mg of naloxone hydrochloride.
One carton containing two REXTOVY Nasal Spray devices: NDC 76329-3669-2
REXTOVY Nasal Spray is not made with natural rubber latex.
Store REXTOVY Nasal Spray in the blister and cartons provided.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 4°C to 40°C (39°F to 104°F). Do not freeze. Protect from light.
Naloxone Hydrochloride freezes at temperatures below -15°C (5°F). If this happens, the device will not spray. If Naloxone Hydrochloride is frozen and is needed in an emergency, do NOT wait for Naloxone Hydrochloride to thaw. Get emergency medical help right away. However, Naloxone Hydrochloride may be thawed by allowing it to sit at room temperature for 15 minutes, and it may still be used if it has been thawed after being previously frozen.
International Medication Systems, Limited So. El Monte, CA 91733, U.S.A. Revised: Jun 2023
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
In two clinical studies, N002-CL-A3 (Study A3) and N002-CL-A4 (Study A4), which comprised a total of 141 study treatments from 60 subjects, including 55 treatments using 4 mg and 10 mg of REXTOVY nasal spray (IN), the following adverse reactions were observed: oral paraesthesia (3.7%), headache (3.7%).
The following adverse reactions have been observed with other naloxone products: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, xeroderma, abdominal pain, asthenia, dizziness, nasal discomfort, and presyncope.
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 signs and symptoms also included convulsions, excessive crying, and hyperactive reflexes [see WARNINGS AND PRECAUTIONS].
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.
No Information provided
Included as part of the PRECAUTIONS section.
The duration of action of most opioids may exceed that of REXTOVY Nasal Spray resulting in a return of respiraÂtory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after administration of REXTOVY Nasal Spray and to keep the patient under continued surveillance. Administer additional doses of REXTOVY Nasal Spray if the patient is not adequately responding or responds and then relapses back into respiratory depression, as necessary [see DOSAGE AND ADMINISTRATION]. Additional supportive and/or resuscitative measures may be helpful while awaitÂing emergency medical assistance.
Reversal of respiratory depression by partial agonists or mixed agonist/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]. Buprenorphine antagonism is charÂacterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.
The use of REXTOVY Nasal Spray in patients who are opioid dependent may precipitate opioid withdrawal charÂacterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezÂing, 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: conÂvulsions, 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, vomitÂing, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrilÂlation, 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. After use of naloxone hydrochloÂride, 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 Populations].
Advise the patient and family members or caregivers to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following:
Instruct patients and their family members or caregivers that, since the duration of action of most opioids may exceed that of REXTOVY Nasal Spray, they must seek immediate emergency medical assistance after administraÂtion of REXTOVY Nasal Spray and keep the patient under continued surveillance [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
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 REXTOVY Nasal Spray, using a new nasal spray device each time [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Instruct patients and their family members or caregivers that the use of REXTOVY Nasal Spray in patients who are opioid dependent may precipitate opioid withdrawal [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Instruct patients and their family members or caregivers to:
Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.
Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberÂration 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.
Reproduction studies conducted in mice and rats at doses 6-times and 12-times, respectively, a human dose of 8 mg/day (two REXTOVY Nasal Sprays) based on body surface area comparison, demonstrated no adverse effects on fertility of naloxone hydrochloride.
Life-sustaining therapy for opioid overdose should not be withheld (see Clinical Considerations). There is an absence of data on naloxone hydrochloride administered for known or suspected opioid overdose in pregnant patients. Available data from retrospective cohort studies on oral naloxone use in pregnant women for opioid use disorder have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. 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 6-times and 12-times, respectively, a human dose of 8 mg/day (two REXTOVY Nasal Sprays) based on body surface area comparison (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
An opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated. Treatment with REXTOVY Nasal Spray for opioid overdose should not be withheld because of potential concerns regarding the effects of REXTOVY Nasal Spray on the fetus.
Animal Data
Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 6-times and 12-times, respectively, a human dose of 8 mg (two REXTOVY Nasal Sprays) based on body surface area comparison. These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.
Naloxone hydrochloride is minimally orally bioavailable and is unlikely to affect the breastfed infant. There is no information regarding the presence of naloxone in human milk, or the effects of naloxone on the breastfed infant or on milk production. Published studies in lactating mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels.
The safety and effectiveness of REXTOVY Nasal Spray have been established in pediatric patients for known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. Use of naloxÂone hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of other naloxone hydrochloride drug products. No pediatric studies were conducted for REXTOVY Nasal Spray.
Absorption of naloxone hydrochloride following intranasal administration in pediatric patients may be erratic or deÂlayed. 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 in 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].
Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availÂability of alternate naloxone-containing products may be better suited than REXTOVY Nasal Spray.
Clinical studies of REXTOVY Nasal Spray did not include sufficient numbers of subjects aged 65 and over to deterÂmine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone hydrochloride can be higher in these patients.
No Information provided
REXTOVY Nasal Spray is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients.
Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.
Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotenÂsion. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.
When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minÂutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of adÂministration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.
In a pharmacokinetic study on healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril (4 mg total dose, 0.25 mL of 16 mg/mL naloxone hydrochloride solution) was compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular (IM) injection, and 2 mg naloxone hydrochloride intravenous (IV) infusion.
The pharmacokinetics parameters obtained in the study are shown in Table 1. The pharmacokinetic curves (0-6 hours and 0-30 minutes, respectively) for REXTOVY Nasal Spray 4 mg by IN and naloxone HCl 0.4 mg delivered by IM and 2 mg naloxone by IV are provided in Figure 2, respectively.
Table 1 : Mean Pharmacokinetic Parameters for Naloxone Following REXTOVY Nasal Spray, IM Injection and IV Infusion of Naloxone HCl to Healthy Subjects
| Parameters | 4 mg REXTOVY Nasal Spray | 0.4 mg Naloxone HCl Intramuscular Injection | 2 mg Naloxone HCl Intravenous Infusion |
| Population | N=25 | N=27 | N=26 |
| AUC0-6h (ng*hr/mL) | 6.41 ± 1.33 | 1.54 ± 1.27 | 8.44 ± 1.34 |
| AUC0-inf (ng*hr/mL) | 6.63 ± 1.32 | 1.60 ± 1.27 | 8.64 ± 1.33 |
| Cmax (ng/mL) | 3.71 ± 1.55 | 0.73 ± 1.56 | 11.10 ± 2.15 |
| tmax (min) | 32.1 ± 1.6 | 24.4 ± 2.4 | 4.9 ± 1.4 |
| t½ (min) | 67.6 ± 1.2 | 75.7 ± 1.2 | 66.2 ± 1.2 |
| Dose-Normalized Relative BA (%) vs. IV | 40.7 ± 17.8 | 95.9 ± 28.5 |
Figure 2: Â Mean Plasma Concentration of Naloxone, (a) 0-6 hrs and (b) 0-1 hour Following Intranasal Administration of REXTOVY Nasal Spray (4mg) and IM Injection of Naloxone HCl (0.4mg) (a) AND (b)
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The dose-normalized relative bioavailability of one (4 mg) dose of REXTOVY Nasal Spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by IV was 40.7%.
Following parenteral administration, naloxone hydrochloride is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone hydrochloride also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.
Following a single intranasal administration of REXTOVY Nasal Spray (4 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone hydrochloride in healthy adults was approximately 67.6 minutes, which was shorter than that observed after administrations of a 0.4 mg naloxone hydrochloride IM injection, where the half-life was 75.7 minutes. The half-life of 2 mg naloxone hydrochloride IV infusion is approximately 66.2 minutes.
Metabolism
Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucuÂronide as the major metabolite.
Excretion
Naloxone is excreted mainly as metabolites in urine.
REXTOVY
(rex toe' vee)
(Naloxone Hydrochloride) Nasal Spray
You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency happens. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about REXTOVY™ Nasal Spray?
REXTOVY™ Nasal Spray is used to temporarily reverse the effects of opioid medicines. The medicine in REXTOVY™ Nasal Spray has no effect in people who are not taking opioid medicines. Always carry REXTOVY™ Nasal Spray with you in case of an opioid emergency.
What is REXTOVY™ Nasal Spray?
Who should not use REXTOVY™ Nasal Spray?
Do not use REXTOVY™ Nasal Spray if you are allergic to naloxone hydrochloride or any of the ingredients in REXTOVY™ Nasal Spray. See the end of this leaflet for a complete list of ingredients in REXTOVY™ Nasal Spray.
What should I tell my healthcare provider before using REXTOVY™ Nasal Spray?
Before using REXTOVY™ Nasal Spray, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I use REXTOVY™ Nasal Spray?
Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use REXTOVY™ Nasal Spray.
What are the possible side effects of REXTOVY™ Nasal Spray?
REXTOVY™ Nasal Spray may cause serious side effects, including:
In infants under 4 weeks old who have been receiving opioids regularly, sudden opioid withdrawal may be life-threatening if not treated the right way. Signs and symptoms include: seizures, crying more than usual, and increased reflexes.
The most common side effects of REXTOVY™ Nasal Spray include tingling in your mouth, and headache.
These are not all of the possible side effects of REXTOVY™ Nasal Spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store REXTOVY™ Nasal Spray?
Keep REXTOVY™ Nasal Spray and all medicines out of the reach of children.
General information about the safe and effective use of REXTOVY™ Nasal Spray.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REXTOVY™ Nasal Spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about REXTOVY™ Nasal Spray that is written for health professionals.
What are the ingredients in REXTOVY™ Nasal Spray?
Active ingredient: naloxone hydrochloride
Inactive ingredients: sodium chloride, sodium hydroxide to adjust pH and water for injection USP REXTOVY™ Nasal Spray is not made with natural rubber latex.
Instructions for Use
REXTOVY
(rex toe’ vee)
(Naloxone Hydrochloride) Nasal Spray
You and your family members or caregivers should read the Instructions for Use that comes with REXTOVY™ 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 REXTOVY™ Nasal Spray.
Use REXTOVY™ Nasal Spray for known or suspected opioid overdose in adults and children.
Important: For use in the nose only.
How to use REXTOVY™ Nasal Spray:
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Note: REXTOVY™ Nasal Spray 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 REXTOVY™ Nasal Spray to thaw. REXTOVY™ Nasal Spray may still be used if it has been thawed after being previously frozen.
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How should I store REXTOVY™ Nasal Spray?
Keep REXTOVY™ Nasal Spray and all medicines out of the reach of children.
Instructions for Use
REXTOVY
(rex toe’ vee)
(Naloxone Hydrochloride)Nasal Spray Unit
You and your family members or caregivers should read the Instructions for Use that comes with REXTOVY™ 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 REXTOVY™ Nasal Spray.
Use REXTOVY™ Nasal Spray for known or suspected opioid overdose in adults and children.
Important: For use in the nose only.
How to use REXTOVY™ Nasal Spray:
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Note: REXTOVY™ Nasal Spray 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 REXTOVY™ Nasal Spray to thaw. REXTOVY™ Nasal Spray maystill be used if it has been thawed after being previously frozen.
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How should I store REXTOVY™ Nasal Spray?
Keep REXTOVY™ Nasal Spray and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
