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REXTOVY Naloxone Hydrochloride 4 mg/.25mL Spray, 25 mL — NDC 76329-3669-02 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

REXTOVY Naloxone Hydrochloride 4 mg/.25mL Spray, 25 mL — NDC 76329-3669-2 (Billing 76329-3669-02)

by International Medication Systems, Ltd. · 2 CONTAINER in 1 CONTAINER / .25 mL in 1 CONTAINER

This is a package of 25 mL of REXTOVY Naloxone Hydrochloride 4 mg/.25mL Spray from International Medication Systems, Ltd., marketed since May 2024 and currently FDA-listed. It is this product's only package size.

NDC 76329-3669-02
🏷️ FDA NDC (as labeled) 76329-3669-2 billing pads the package segment with a zero
Rx only Brand On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 76329-3669-2 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
76329 labeler · 3669 product · 2 package
Package marketed since
May 7, 2024
Sample package
No — commercial package
Listing certified through
Dec 31, 2026
Barcode (UPC-A, from the NDC)
3 7632936692 0
Medicaid fills, this package
673 prescriptions in the last four reported quarters
FDA record last changed
Jul 24, 2026

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 76329-3669-2
Product NDC 76329-3669
11-digit billing NDC 76329366902
NCPDP billing unit EA — each (per item)
RxCUI 2637879, 2680741
UNII F850569PQR
Application # NDA208969
SPL Set ID fe9735db-c57e-44a8-bffb-b87a84c2a6f3
Established class (EPC) Opioid Antagonist
Mechanism of action Opioid Antagonists
DEA schedule Non-controlled
Marketing category NDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2024-05-07
Route NASAL
Dosage form SPRAY
Substance NALOXONE HYDROCHLORIDE

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 93400020100922
GCN Seq No 075222
GCN 40233
HICL code 001874
Ingredient (HICL) Naloxone Hcl
HIC1 code H
Therapeutic class — broad (HIC1) Nervous System (Except Autonomic)
HIC2 code H3
Therapeutic class — intermediate (HIC2) Analgesics
HIC3 code H3T
Therapeutic class — specific (HIC3) Opioid Antagonists
AHFS code 28:10.00.00
AHFS class Opioid Antagonists (28:10)
FDB label name REXTOVY 4 MG NASAL SPRAY
FDB brand name Rextovy
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 075222
  • GCN: 40233
  • GPI-14 (Medi-Span): 93400020100922
  • HICL (First Databank): 001874
  • AHFS class code: 28:10.00.00
  • RxCUI (RxNorm): 2637879
Why two NDCs? The FDA registers this code as 76329-3669-2 — a 5-4-1 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the package segment → 76329-3669-02. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Opioid Antagonist class.

Pharmacologic class Opioid Antagonist
Drug family (ATC) Other opioids, Natural opium alkaloids, Benzomorphan derivatives
How it works Opioid Antagonists
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name REXTOVY 4 MG NASAL SPRAY Ingredient Naloxone Hcl
📖 What it is MedlinePlus · NLM

Naloxone nasal spray is used along with emergency medical treatment to reverse the life-threatening effects of a known or suspected opiate (narcotic) overdose. Naloxone nasal spray is in a class of medications called opiate antagonists. It works by blocking the effects of opiates to relieve dangerous symptoms caused by high levels of opiates in the blood.

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • It is an emergency medicine that reverses an opioid overdose. Signs include very slow or stopped breathing and being unresponsive. Some injection forms have extra hospital or milit...
  • Follow the instructions that came with your product. Nasal sprays go into one nostril. Zimhi goes into the outer thigh. Call 911 right away. If the person does not wake up or slips...
  • Naloxone can wear off before the opioid does. Breathing problems can come back. Stay with the person until emergency help arrives.
  • Why do I still need to call 911 if they wake up?
📖 Read our full Naloxone guide →

Supplement & herbal interactions

Some supplements/herbs that may interact with Naloxone Hydrochloride — tap one for details:

1,4-butanediolModerate Gamma Butyrolactone (gbl)Moderate Gamma-hydroxybutyrate (ghb)Moderate
🌿 Every supplement checked against Naloxone Hydrochloride (3 interactions) — ranked by severity →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer mLPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo $22.40 $11.20 / 0.5 ml
Medicare drug plans payPart D · Q2 2026 $22.52 $11.26 / 0.5 ml
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
76329-3669-02 You're viewing this Main listing 2 CONTAINER in 1 CONTAINER / .25 mL in 1 CONTAINER 2024-05-07 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Rextovy 4 mg/.25mLthis 76329-3669-02 International 25 ml — — FDA listed —
About this product: this is the brand-name version. FDA-approved generic versions are listed, and recent pricing/market data suggests they may be available.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2023
First FDA approval
Mar 2023
📍
2026
Currently FDA-listed
3 years listed
🔓
·
Listed protection lapsed
listed protections lapsed 2026
✅Generic appears available

FDA-approved generic versions are listed, and recent pricing/market data suggests they may be available — see Therapeutic equivalents.

🛡️ Latest patent/protection date listed: The latest listed FDA patent/protection lapsed Mar 2026 — those protections no longer apply, though a generic still needs FDA approval and a manufacturer to market it.
📅 FDA approved Mar 7, 2023 RLD RS

Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.

Patents & exclusivity — FDA Orange Book
Exclusivity NP
2023 2025
Today
LOE
Substance patent Formulation patent Method-of-use patent Exclusivity Pediatric +6mo
🏛️FDA exclusivity
FDA-granted marketing protection. It’s separate from patents and may be shorter than patent protection.
🧪Product / substance patents
Patents covering the active ingredient, product, formulation, or related drug features.
🎯Method-of-use patents
Patents covering specific approved uses. These can sometimes be carved out with a “skinny label,” but not always.
🛈 What do these terms mean?
Patent
Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
Substance patent
Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
Formulation (product) patent
Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
Method-of-use patent
A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
Skinny label
A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
Exclusivity
FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
Paragraph IV
A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
RLD / RS
Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
TE / AB rating
FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
LOE (loss of exclusivity)
The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.

Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.

FDA exclusivity
CodeWhat it grantsExpires
NPNew ProductMar 7, 2026
Common questions
Is there a generic version of REXTOVY 4 MG NASAL SPRAY?
Yes — an FDA-approved generic equivalent is listed in the FDA Orange Book for REXTOVY 4 MG NASAL SPRAY. See the alternatives section for substitutable, lower-cost products.
The FDA approved a generic — why can’t I get it at my pharmacy yet?
FDA approval and pharmacy availability are two different things. The FDA can approve a generic years before it actually reaches pharmacies, because the brand company may still hold patents or have a settlement that delays the launch. A manufacturer also has to choose to make and sell it, and have supply ready. So a drug can be “FDA-approved generic exists” and still be brand-only at the counter today.
Why do different websites show different generic release dates?
Generic availability is not based on one single date. Some sources use the first exclusivity expiration, some use the last product patent, and others use the latest method-of-use patent. Patent challenges, settlements, licenses, and label carve-outs can also change the real-world launch date. This page shows the underlying Orange Book dates so you can see why estimates may differ.
What does “FDA listed” mean?
It means the product appears in the FDA’s official NDC directory. That’s a good sign a product exists and is intended for the U.S. market, but on its own it does not confirm a pharmacy can fill it today. Where we have recent retail pricing data (NADAC) for a product, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Orange Book for a patent or exclusivity on the brand product. It can affect when a full generic version becomes widely available — but it is not a guaranteed generic launch date. Generics sometimes arrive earlier (through a settlement or patent challenge) or later (a manufacturer still has to make and sell one).
What does “current Orange Book estimate” mean?
It means we are using the latest patent and exclusivity dates currently listed in the FDA Orange Book. It is not a guaranteed launch date.
Can a generic come out before the last patent expires?
Sometimes. A generic company may challenge a patent, settle with the brand manufacturer, receive a license, or obtain approval with a narrower label that avoids a patented use. In other cases, the last listed protection may delay full-label generic competition.
Can a generic come out after the listed dates?
Yes. Even after patents or exclusivity expire, a generic still needs FDA approval and a manufacturer must choose to market it. Supply, litigation, business decisions, or regulatory issues can delay actual availability.
What is the difference between patents and exclusivity?
Patents are legal protections usually issued by the U.S. Patent and Trademark Office. FDA exclusivity is marketing protection granted by the FDA. They are separate, and either one can affect generic timing.
Why are there multiple patent dates?
One drug can have several patents covering different things: the active ingredient, a formulation, a manufacturing process, or a specific approved use. That is why a page may show several expiration dates instead of one simple generic date.
Built from FDA Orange Book patent and exclusivity data. Dates are refreshed from public FDA data when available; the marker is max(latest patent expiry, latest exclusivity expiry). Paragraph-IV settlements and first-filer 180-day exclusivity can shift the real date; a method-of-use patent may allow an earlier skinny-label generic for non-protected indications. Generic launch timing is an estimate, not a guarantee.
Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII 451W47IQ8X
    Sodium chloride is common table salt. It's used in medicines as a buffer to maintain proper pH, as a filler to add bulk, or to adjust the osmotic balance in liquid formulations.
  • UNII 55X04QC32I
    A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
  • UNII 059QF0KO0R
    Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.

3 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerInternational Medication Systems, Ltd.
Application holderAMPHASTAR PHARMACEUTICALS INC
FDA applicationNDA208969 (NDA)
Labeler code76329
First marketedMay 2024
Product typeHuman Prescription Drug

More NDCs from International Medication Systems, Ltd. labeler code 76329

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📦 Storage and Handling 📋 Description 💬 Information for Patients 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📖 Instructions for Use 📄 Package Label / Principal Display Panel
🎯 Indications and Usage 131 words ▾

1 INDICATIONS AND USAGE 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.

REXTOVY Nasal Spray is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression for adults and pediatric patients. ( 1 ) REXTOVY Nasal Spray is intended for immediate administration as emergency therapy in settings where opioids may be present. ( 1 ) REXTOVY Nasal Spray is not a substitute for emergency medical care.

( 1 )

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION REXTOVY Nasal Spray is for intranasal use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administer one spray of REXTOVY Nasal Spray to adults or pediatric patients intranasally into one nostril.

( 2.2 ) Administer additional doses of REXTOVY Nasal Spray using a new nasal spray device with each dose if the patient does not respond or responds and then relapses into respiratory depression. Additional doses of REXTOVY Nasal Spray may be given every 2 to 3 minutes until emergency medical assistance arrives. ( 2.2 ) Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

( 2.2 )

2.1Important Administration Instructions REXTOVY Nasal Spray is for intranasal use only. The device is ready to use. Do not prime or test prior to administration.

Do not attempt to reuse REXTOVY Nasal Spray. Each unit-dose device contains a single dose of naloxone and cannot be reused. Figure 1 REXTOVY Nasal Spray Device Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of REXTOVY Nasal Spray and the Instructions for Use .

Instruct the users or caregiver to read the Instructions for Use at the time they receive a prescription for REXTOVY Nasal Spray. Emphasize the following instructions to the patient or caregiver: Administer REXTOVY Nasal Spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Always seek immediate emergency medical assistance after the first dose of REXTOVY Nasal Spray has been administered in the event of a suspected, potentially life-threatening opioid emergency because the duration of action of most opioids exceeds that of naloxone hydrochloride.

Keep the patient under continued surveillance and administer repeated doses of REXTOVY Nasal Spray, as necessary, until emergency personnel arrive [see Warnings and Precautions ( 5.1 )] . Administer REXTOVY Nasal Spray according to the printed instructions on the carton and the Instructions for Use . ◦ Place the patient in the supine position. Prior to administration, be sure the device nozzle is inserted in either nostril of the patient and provide support to the back of the neck to allow the head to tilt back.

Do not prime or test the device prior to administration. ◦To administer the dose, press firmly on the green plunger of the device and remove the REXTOVY Nasal Spray nozzle from the nostril after use. ◦If the patient responds by waking up to the voice or touch or starts breathing normally, place the person on their side (recovery position) as shown in the Instructions for Use and call for emergency medical assistance immediately after the first dose of REXTOVY Nasal Spray. ◦Administer additional doses of REXTOVY Nasal Spray, using a new REXTOVY Nasal Spray, every 2 to 3 minutes as needed if the patient does not respond or responds and then relapses into respiratory depression.

Administer REXTOVY Nasal Spray in alternate nostrils with each dose [see Dosing and Administration ( 2.2 )] . figure1

2.2Dosing in Adults and Pediatric Patients Initial Dosing 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. Repeat Dosing Seek emergency medical assistance as soon as possible after administering the REXTOVY Nasal Spray. The requirement 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 REXTOV… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 55 words ▾

3 DOSAGE FORMS AND STRENGTHS 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. 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

⛔ Contraindications 34 words ▾

4 CONTRAINDICATIONS REXTOVY Nasal Spray is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients. Hypersensitivity to naloxone hydrochloride or to any of the other ingredients.

⚠️ Warnings and Cautions ~3 min read ▾

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 device with each dose, as necessary, while awaiting emergency medical assistance. ( 5.1 ) Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete.

Larger or repeat doses may be required. ( 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 REXTOVY Nasal Spray. ( 5.3 )

5.1Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of REXTOVY Nasal Spray 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 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 ( 2.2 )] .

Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

5.2Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists 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 ( 2.3 )] . Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

5.3Precipitation of Severe Opioid Withdrawal The use of REXTOVY Nasal Spray in patients who are opioid dependent may precipitate opioid withdrawal 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: convulsions, 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. After use of naloxone hydrochloride, moni… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~2 min read ▾

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 observed in a REXTOVY Nasal Spray clinical study: oral paraesthesia (3.7%), headache (3.7%) ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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. 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.

6.2Postmarketing 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 signs and symptoms also included convulsions, excessive crying, and 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.

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary 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.

Clinical Considerations 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. Data 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.

8.2Lactation Risk Summary 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.

8.4Pediatric Use 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 naloxone 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 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 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… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~1 min read ▾

8.1Pregnancy Risk Summary 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.

Clinical Considerations 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. Data 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.

🧒 Pediatric Use ~1 min read ▾

8.4Pediatric Use 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 naloxone 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 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 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 ( 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 REXTOVY Nasal Spray.

🧓 Geriatric Use 79 words ▾

8.5Geriatric Use Clinical studies of REXTOVY Nasal Spray 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. 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.

🧬 Clinical Pharmacology ~2 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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 hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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. Absorption 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 in 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 AUC 0-6h (ng*hr/mL ) 6.41 ± 1.33 1.54 ± 1.27 8.44 ±

1.34AUC 0-inf (ng*hr/mL ) 6.63 ± 1.32 1.60 ± 1.27 8.64 ±

1.33C max (ng/mL) 3.71 ± 1.55 0.73 ± 1.56 11.10 ± 2.15 t max (min) 32.1 ± 1.6 24.4 ± 2.4 4.9 ± 1.4 t ½ (min) 67.6 ± 1.2 75.7 ± 1.2 66.2 ±

1.2Dose-Normalized Relative BA (%) vs. IV 40.7 ± 17.8 95.9 ± 28.5 --- Figure 2 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) (b) T he 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%. Distribution 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.

Elimination 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-glucuronide as the major metabolite.

Excretion Naloxone is excreted mainly as metabolites in urine. figure2a figure2b

🧬 Mechanism of Action 48 words ▾

12.1Mechanism of Action 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 hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

📦 How Supplied / Storage and Handling 203 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1How Supplied 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.

16.2Storage and Handling 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.

16.1How Supplied 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.

📦 Storage and Handling 110 words ▾

16.2Storage and Handling 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.

📋 Description 154 words ▾

11 DESCRIPTION Naloxone hydrochloride is an opioid antagonist. It is chemically identified as 17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate. Its molecular formula is C 19 H 21 NO 4 • HCl • 2H 2 O and has a molecular weight of 399.87 g/mol.

It has the following structural formula: 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. structure

💬 Information for Patients ~3 min read ▾

17 PATIENT COUNSELING INFORMATION 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, since the duration of action of most opioids may exceed that of REXTOVY Nasal Spray, they must seek immediate emergency medical assistance after administration of REXTOVY Nasal Spray 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 REXTOVY Nasal Spray, using a new nasal spray device each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)] . Precipitation of Severe Opioid Withdrawal 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 (5.3), Adverse Reactions (6)] .

Administration Instructions Instruct patients and their family members or caregivers to: Ensure REXTOVY Nasal Spray is readily available in locations where persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies). Use each REXTOVY Nasal Spray device only one time. Do not test or prime prior to use [see Dosage and Administration (2.1)] .

Administer REXTOVY Nasal Spray 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. REXTOVY Nasal Spray is not a substitute for emergency medical care [see Dosage and Administration (2.1)] . Lay the patient on their back and administer REXTOVY Nasal Spray 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)] .

If the patient responds by waking up to the voice or touch or starts breathing normally, place them in the recovery position by turning them to their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of REXTOVY Nasal Spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)] . Monitor the patient and re-administer additional doses of REXTOVY Nasal Spray every 2 to 3 minutes, using a new REXTOVY Nasal Spray device.

If the patient is not responding or responds and then relapses back into respiratory depression, administer REXTOVY Nasal Spray in alternate nostrils with each dose [see Dosage and Administration (2.1)] . Replace REXTOVY Nasal Spray before its expiration date.

PATIENT INFORMATION 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 medica… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacokinetics ~2 min read ▾

12.3Pharmacokinetics 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. Absorption 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 in 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 AUC 0-6h (ng*hr/mL ) 6.41 ± 1.33 1.54 ± 1.27 8.44 ±

1.34AUC 0-inf (ng*hr/mL ) 6.63 ± 1.32 1.60 ± 1.27 8.64 ±

1.33C max (ng/mL) 3.71 ± 1.55 0.73 ± 1.56 11.10 ± 2.15 t max (min) 32.1 ± 1.6 24.4 ± 2.4 4.9 ± 1.4 t ½ (min) 67.6 ± 1.2 75.7 ± 1.2 66.2 ±

1.2Dose-Normalized Relative BA (%) vs. IV 40.7 ± 17.8 95.9 ± 28.5 --- Figure 2 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) (b) T he 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%. Distribution 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.

Elimination 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-glucuronide as the major metabolite.

Excretion Naloxone is excreted mainly as metabolites in urine. figure2a figure2b

🧬 Pharmacodynamics 52 words ▾

12.2Pharmacodynamics 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.

🧪 Nonclinical Toxicology 109 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed. 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 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.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 106 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed. 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 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.

📖 Instructions for Use ~1 min read ▾

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. Do not remove or test the REXTOVY™ Nasal Spray until ready to use. Each REXTOVY™ Nasal Spray has 1 dose and cannot be reused.

You do not need to prime REXTOVY™ Nasal Spray. How to use REXTOVY™ Nasal Spray: How should I store REXTOVY™ Nasal Spray? Store at room temperature between 68°F to 77°F (20°C to 25°C).

REXTOVY™ Nasal Spray may be stored for short periods between 39°F to 104°F (4°C to 40°C). Do not freeze. Do not expose to temperatures below 39°F (4°C) or above 104°F (40°C).

Keep REXTOVY™ Nasal Spray in its box until ready to use. Protect from light. Replace REXTOVY™ Nasal Spray before the expiration date on the box.

Keep REXTOVY™ Nasal Spray and all medicines out of the reach of children. Distributed by International Medication Systems, Limited, So. El Monte, CA 91733, U.S.A.

For more information, go to www.amphastar.com or call 1-800-423-4136. This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Issued: 06/2023 7036690F/6-23 IFUInstruction

📄 Package Label / Principal Display Panel 108 words ▾

Carton Label Principal Display Panel Text: NDC 76329- 3669 -2 Rx Only REXTOVY™ (Naloxone HCl) Nasal Spray 4 mg per Device For use in the Nose Only USE FOR KNOWN OR SUSPECTED OPIOID OVERDOSE Seek Emergency Medical Attention See Instructions for Use for Administration. This box contains two (2) unit-dose 4 mg NASAL Spray devices. Deliver full dose into one nostril 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 excessive heat Protect from light INTERNATIONAL MEDICATION SYSTEMS, LIMITED So. El Monte, CA 91733, U.S.A. An Amphastar Pharmaceuticals Company www.Amphastar.com 5636690D/3-23 Stock No.

3669 carton

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicaid utilization & spend

📍 This exact package only: Medicaid data is reported per full 11-digit NDC — labeler, product and pack size — so every number here is for this package alone, not the drug overall. Other pack sizes report separately.
💊 Pharmacy benefit only: These are Medicaid outpatient pharmacy claims, billed by NDC. They exclude the medical benefit — clinic- or hospital-administered drugs billed under HCPCS J-codes — so drugs used mostly that way (e.g. Avastin, Lucentis, Keytruda) can look low or missing here. That’s expected, not an error.
📅 Q1 2025 – Q1 2026 · 5 quarters of data
ⓘ The newest quarter is usually incomplete when first published; states restate recent quarters in later CMS releases, so the latest figures typically revise upward. State coverage-policy changes can also shift quarter-to-quarter totals.
Prescriptions last 4 qtrs
673
Units reimbursed last 4 qtrs
1.5K
Gross reimbursed last 4 qtrs
$32.6K
Avg / prescription
$48.49
Avg / unit
$22.4000
Latest quarter Q1 2026
97Rx
Fee-for-service vs managed care ⓘ
32% FFS 68% MCO
Fee-for-service · 217 Rx Managed care · 456 Rx
State Medicaid map
Alaska: no data reported AK Maine: no data reported ME Washington: no data reported WA Idaho: no data reported ID Montana: no data reported MT North Dakota: no data reported ND Minnesota: no data reported MN Wisconsin: no data reported WI Michigan: no data reported MI New York: 144 units · 0.7 per 100k residents NY Vermont: no data reported VT New Hampshire: no data reported NH Oregon: no data reported OR Nevada: no data reported NV Wyoming: no data reported WY South Dakota: no data reported SD Iowa: no data reported IA Illinois: 144 units · 1.1 per 100k residents IL Indiana: 105 units · 1.5 per 100k residents IN Ohio: 38 units · 0.3 per 100k residents OH Pennsylvania: no data reported PA New Jersey: no data reported NJ Massachusetts: no data reported MA California: no data reported CA Utah: no data reported UT Colorado: 192 units · 3.3 per 100k residents CO Nebraska: no data reported NE Missouri: no data reported MO Kentucky: no data reported KY West Virginia: no data reported WV Virginia: 118 units · 1.4 per 100k residents VA Maryland: 94 units · 1.5 per 100k residents MD Connecticut: no data reported CT Rhode Island: no data reported RI Arizona: 102 units · 1.4 per 100k residents AZ New Mexico: 62 units · 2.9 per 100k residents NM Kansas: no data reported KS Arkansas: no data reported AR Tennessee: no data reported TN North Carolina: 160 units · 1.5 per 100k residents NC South Carolina: no data reported SC Delaware: no data reported DE Oklahoma: no data reported OK Louisiana: no data reported LA Mississippi: no data reported MS Alabama: no data reported AL Georgia: no data reported GA D.C.: 132 units · 19.4 per 100k residents DC Hawaii: no data reported HI Texas: 166 units · 0.5 per 100k residents TX Florida: no data reported FL
Units reimbursed · per 100k residents
0.319.4
gray = no data reported ⓘ
Colors are per 100,000 residents, so big states don’t automatically dominate. Tap or hover a state for its actual totals.
Tap or hover a state
…for its Medicaid breakdown
🏆 Top states by units · per 100k residents
1 D.C. 19.4 /100k
2 Colorado 3.3 /100k
3 New Mexico 2.9 /100k
4 Indiana 1.5 /100k
5 Maryland 1.5 /100k
6 North Carolina 1.5 /100k
7 Arizona 1.4 /100k
8 Virginia 1.4 /100k
National units — by quarter
💵 About the dollar figures: “reimbursed” is what Medicaid paid pharmacies before confidential manufacturer rebates, so the program’s real net cost is lower than these numbers. Fee-for-service and managed-care claims are combined unless split above. Source: CMS State Drug Utilization Data; per-100k rates use 2023 Census population estimates.

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Rextovy — the program that covers self-administered drugs. 1 manufacturer.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Rextovy. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$33.9K
Claims incl. refills
767
Beneficiaries
753
Spend / beneficiary
$45.07
Spend / claim
$44.24
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for REXTOVY (this brand).

Top reported reactions

Toxicity To Various Agents82
Vomiting58
Fatigue48
Drug Withdrawal Syndrome46
Overdose46
Nausea44
Diarrhoea40

Reporter sex

0 reports

Serious outcomes

Death137
Disabling12
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 128 45
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.

About this NDC listing & data coverage

Finished prescription product
What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos ✓ Available
Inactive ingredients (structured) ✓ Available
NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data ✓ Available
HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
Medicaid utilization (CMS SDUD) ✓ Available
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by International Medication Systems, Ltd.. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
International Medication Systems, Ltd. is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 76329-3469-01 · International 76329-6300-05 · International →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.