Naloxone hydrochloride nasal spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression." }

Naloxone hydrochloride nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present.

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present." }

Naloxone hydrochloride nasal spray is not a substitute for emergency medical care.

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is not a substitute for emergency medical care." }

Naloxone hydrochloride nasal spray is for intranasal use only.

No additional device assembly is required.

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 naloxone hydrochloride nasal spray and the Instructions for Use.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for naloxone hydrochloride nasal spray. Emphasize the following instructions to the patient or caregiver:

Initial Dosing

The recommended initial dose of naloxone hydrochloride nasal spray in adults and pediatric patients is one spray delivered by intranasal administration into one nostril.

Repeat Dosing

Seek emergency medical assistance as soon as possible after administering the first dose of naloxone hydrochloride nasal spray. 

The requirement for repeat doses of naloxone hydrochloride nasal spray depends upon the amount, type, and route of administration of the opioid being antagonized.

Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose.

If the patient responds to naloxone hydrochloride nasal spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray and continue surveillance of the patient.

If the desired response is not obtained after 2 or 3 minutes, administer an additional dose of naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray. If there is still no response and additional doses are available, administer additional doses of naloxone hydrochloride nasal spray every 2 to 3 minutes using a new naloxone hydrochloride nasal spray 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 pentazocine, may be incomplete and require higher doses of naloxone hydrochloride or repeated administration of naloxone hydrochloride nasal spray using a new nasal spray [see Warnings and Precautions (5.2)].

Naloxone hydrochloride nasal spray is supplied as a single-dose intranasal spray containing 4 mg of naloxone hydrochloride in 0.1 mL.

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is supplied as a single-dose intranasal spray containing 4 mg of naloxone hydrochloride in 0.1 mL." }

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

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients." }

The duration of action of most opioids may exceed that of naloxone hydrochloride 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 the first dose of naloxone hydrochloride nasal spray and to keep the patient under continued surveillance. Administer additional doses of naloxone hydrochloride 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.

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.

The use of naloxone hydrochloride 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. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, 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, naloxone­containing product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Populations (8.4)].

The following serious adverse reactions are discussed elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are discussed elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)]\n" ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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." }

The following adverse reactions were observed in a naloxone hydrochloride nasal spray clinical study.

{ "type": "p", "children": [], "text": "The following adverse reactions were observed in a naloxone hydrochloride nasal spray clinical study." }

In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of naloxone hydrochloride nasal spray in one nostril or two sprays of naloxone hydrochloride nasal spray, one in each nostril, the most common adverse reactions were: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma.

{ "type": "p", "children": [], "text": "In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of naloxone hydrochloride nasal spray in one nostril or two sprays of naloxone hydrochloride nasal spray, one in each nostril, the most common adverse reactions were: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma." }

The following adverse reactions have been identified primarily during post-approval use of naloxone hydrochloride in the post-operative 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 post-operative patients have resulted in significant reversal of analgesia, and have caused agitation.

{ "type": "p", "children": [], "text": "The following adverse reactions have been identified primarily during post-approval use of naloxone hydrochloride in the post-operative 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 post-operative 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 may be 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.

{ "type": "p", "children": [], "text": "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 may be 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." }

Risk Summary

The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times, respectively, a human dose of 8 mg/day (two naloxone hydrochloride 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

Fetal/Neonatal adverse reactions

Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother [see Warnings and Precautions (5.3)]. The fetus should be evaluated for signs of distress after naloxone hydrochloride nasal spray is used. Careful monitoring is needed until the fetus and mother are stabilized.

Data

Animal Data

Naloxone hydrochloride was administered during organogenesis to mice and rats at subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a human dose of 8 mg (two naloxone hydrochloride nasal sprays) (based on body surface area comparison). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

Pregnant female rats were administered 2 or 10 mg/kg naloxone subcutaneously from Gestation Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison).

Risk Summary

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. Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable.

The safety and effectiveness of naloxone hydrochloride nasal spray have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in 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 naloxone hydrochloride 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. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening, if not recognized, and should be treated according to protocols developed by neonatology experts [see Warnings and Precautions (5.3)].

In settings such as in neonates with known or suspected exposure to maternal opioid use, where it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of an alternate naloxone-containing product that can be dosed according to weight and titrated to effect.

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 naloxone hydrochloride nasal spray.

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 studies of naloxone hydrochloride 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.

Naloxone hydrochloride nasal spray is a pre-filled, single dose intranasal spray. Chemically, naloxone hydrochloride dihydrate is the hydrochloride salt of (5R,9R,13S,14S)-17-Allyl-3,14-dihydroxy-4,5-epoxymorphinan-6-on hydrochloride dihydrate with the following structure:

{ "type": "p", "children": [], "text": "Naloxone hydrochloride nasal spray is a pre-filled, single dose intranasal spray. Chemically, naloxone hydrochloride dihydrate is the hydrochloride salt of (5R,9R,13S,14S)-17-Allyl-3,14-dihydroxy-4,5-epoxymorphinan-6-on hydrochloride dihydrate with the following structure:" }

C19H22NO4Cl•2H2O M.W. 399.87

{ "type": "p", "children": [], "text": "C19H22NO4Cl•2H2O M.W. 399.87" }

Naloxone hydrochloride, USP an opioid antagonist, occurs as a white to slightly off-white powder, and is freely soluble in water, soluble in ethanol (96%) and practically insoluble in toluene.

{ "type": "p", "children": [], "text": "Naloxone hydrochloride, USP an opioid antagonist, occurs as a white to slightly off-white powder, and is freely soluble in water, soluble in ethanol (96%) and practically insoluble in toluene." }

Each naloxone hydrochloride nasal spray contains a 4 mg single dose of naloxone hydrochloride, USP (equivalent to 3.6 mg of naloxone) in a 0.1 mL (100 microliter) aqueous solution.

{ "type": "p", "children": [], "text": "Each naloxone hydrochloride nasal spray contains a 4 mg single dose of naloxone hydrochloride, USP (equivalent to 3.6 mg of naloxone) in a 0.1 mL (100 microliter) aqueous solution. " }

Inactive ingredients include benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water. The pH range is 3.5 to 5.5.

{ "type": "p", "children": [], "text": "Inactive ingredients include benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water. The pH range is 3.5 to 5.5." }

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.

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.

In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril, (4 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril) was compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray, and remained fully supine for approximately one hour post-dose. For intramuscular administration, naloxone was administered as a single injection in the gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in Table 1.

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0"> <col width="522.9pt"/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Bold">Table 1</span><span class="Bold"> Mean Pharmacokinetic Parameters (CV%) for Naloxone Following Naloxone HCl Nasal Spray and Intramuscular Injection of Naloxone HCl to Healthy Subjects</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Parameter</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold"> </span> </p> <p> <span class="Bold">4 mg – One Nasal Spray in one nostril<br/> </span><span class="Bold">40 mg/ml<br/> </span><span class="Bold">(N=29)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">8 mg – Two Nasal Sprays, one in each nostril<br/> </span><span class="Bold">40 mg/ml<br/> </span><span class="Bold">(N=29)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">0.4 mg<br/> </span><span class="Bold">Intramuscular Injection<br/> </span><span class="Bold">(N=29)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">t<span class="Sub">max</span> (h)</span><span class="Sup">†</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.50 (0.17, 1.00)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.33 (0.17, 1.00)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.38 (0.08, 2.05)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">C<span class="Sub">max</span> (ng/mL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4.83 (43)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">9.70 (36)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0.88 (31)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">AUC<span class="Sub">t</span> (<span class="Bold">hr.ng/mL</span>)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7.87 (37)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15.3 (23)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.75 (23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">AUC<span class="Sub">0-inf</span> (h*ng/mL)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7.95 (37)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15.5 (23)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.79 (23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">t<span class="Sub">1/2</span> (h)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.08 (30)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2.10 (32)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1.24 (26)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Dose normalized Relative BA <br/> (%) vs. IM</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">44.2 (31)<span class="Sup">††</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">43.1 (24)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">100</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Sup">†</span> t<span class="Sub">max</span> reported as median (minimum, maximum)<br/> <span class="Sup">††</span> N=28 for Relative BA.</p> </td> </tr> </tbody> </table></div>

Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0 to 6 h and (b) 0 to 1h Following Intranasal Administration and Intramuscular Injection

The median naloxone tmax after intranasal administration of naloxone hydrochloride nasal spray (one nasal spray in one nostril or two nasal sprays as one spray in each nostril was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride intramuscular injection (Table 1).

The dose normalized relative bioavailability of one dose (4 mg) or two doses (8 mg) of naloxone hydrochloride nasal spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by intramuscular injection was 44% and 43%, respectively.

Distribution

Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

Elimination

Following a single intranasal administration of naloxone hydrochloride nasal spray (4 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 2.08 (30% CV) hours; respectively, which was longer than that observed after administrations of a 0.4 mg naloxone hydrochloride intramuscular injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of naloxone hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.

Metabolism

Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.

Excretion

After an oral or intravenous dose, about 25 to 40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.

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

Male rats were treated with 2 or 10 mg/kg naloxone for 60 days prior to mating. Female rats treated for 14-days prior to mating and throughout gestation with the same doses of naloxone (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison). There was no adverse effect on fertility.

Naloxone hydrochloride nasal spray 4 mg is supplied as a carton containing two blister packages (NDC 0591-2971-99) each with a single spray device.

Naloxone hydrochloride nasal spray is not made with natural rubber latex.

Store naloxone hydrochloride nasal spray in the blister and cartons provided.

Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive heat above 104°F (40°C). Protect from light.

Naloxone hydrochloride nasal spray freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. If naloxone hydrochloride nasal spray is frozen and is needed in an emergency, do NOT wait for naloxone hydrochloride nasal spray to thaw.

Get emergency medical help right away. However, naloxone hydrochloride nasal spray 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.

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

{ "type": "p", "children": [], "text": "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

{ "type": "p", "children": [], "text": "\nRecognition of Opioid Overdose\n" }

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

{ "type": "p", "children": [], "text": "Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following:" }

{ "type": "ul", "children": [ "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:\nMiosis.\nBradycardia and/or hypotension.\n\n" ], "text": "" }

Risk of Recurrent Respiratory and Central Nervous System Depression

{ "type": "p", "children": [], "text": "\nRisk of Recurrent Respiratory and Central Nervous System Depression\n" }

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

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers that, since the duration of action of most opioids may exceed that of naloxone hydrochloride nasal spray, they must seek immediate emergency medical assistance after the first dose of naloxone hydrochloride 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

{ "type": "p", "children": [], "text": "\nLimited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists\n" }

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 naloxone hydrochloride nasal spray, using a new nasal spray each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "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 naloxone hydrochloride nasal spray, using a new nasal spray each time [see Dosage and Administration (2.3), Warnings and Precautions (5.2)]." }

Precipitation of Severe Opioid Withdrawal

{ "type": "p", "children": [], "text": "\nPrecipitation of Severe Opioid Withdrawal\n" }

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

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers that the use of naloxone hydrochloride nasal spray in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions (5.3), Adverse Reactions (6)]." }

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Instruct patients and their family members or caregivers to:

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers to:" }

{ "type": "ul", "children": [ "Ensure naloxone hydrochloride nasal spray is present whenever persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).", "Administer naloxone hydrochloride 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. Naloxone hydrochloride nasal spray is not a substitute for emergency medical care [see Dosage and Administration (2.1)].", "Lay the patient on their back and administer naloxone hydrochloride 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)].", "Use each nasal spray only one time [see Dosage and Administration (2.1)].", "Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration (2.1)].", "Monitor patients and re-administer naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray every 2 to 3 minutes, if the patient is not responding or responds and then relapses back into respiratory depression. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose [see Dosage and Administration (2.1)].", "Replace naloxone hydrochloride nasal spray before its expiration date." ], "text": "" }

Teva Pharmaceuticals USA, Inc. North Wales, PA 19454

{ "type": "p", "children": [], "text": "\nTeva Pharmaceuticals USA, Inc.\nNorth Wales, PA 19454" }

Rev. B 4/2023

{ "type": "p", "children": [], "text": "Rev. B 4/2023" }

<div class="scrollingtable"><table> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PATIENT INFORMATION</span> </p> <p> <span class="Bold">Naloxone Hydrochloride (nal ox’ one hye” droe klor’ ide)</span> </p> <p> <span class="Bold">Nasal Spray</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">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.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about naloxone hydrochloride nasal spray? </span> </p> <p>Naloxone hydrochloride nasal spray is used to temporarily reverse the effects of opioid medicines. The medicine in naloxone hydrochloride nasal spray has no effect in people who are not taking opioid medicines. Always carry naloxone hydrochloride nasal spray with you in case of an opioid emergency.</p> <p>1.  Use naloxone hydrochloride nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:</p> <ul class="Disk"> <li>unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the middle of their chest (sternum)</li> <li>breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing</li> <li>the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called “pinpoint pupils,” in someone difficult to awaken</li> </ul> <p>2.  Family members, caregivers, or other people who may have to use naloxone hydrochloride nasal spray in an opioid emergency should know where naloxone hydrochloride nasal spray is stored and how to give naloxone hydrochloride before an opioid emergency happens.</p> <p>3.  <span class="Bold">Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray.</span> Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. </p> <p>4.  The signs and symptoms of an opioid emergency can return after naloxone hydrochloride nasal spray is given. If this happens, give another dose after 2 to 3 minutes using a new naloxone hydrochloride nasal spray and watch the person closely until emergency help is received.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is naloxone hydrochloride nasal spray?</span> </p> <ul class="Disc"> <li>Naloxone hydrochloride nasal spray is a prescription medicine used for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.</li> <li>Naloxone hydrochloride nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray, even if the person wakes up. </li> <li>Naloxone hydrochloride nasal spray is safe and effective in children for known or suspected opioid overdose.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Who should not use naloxone hydrochloride nasal spray? </span> </p> <p> <span class="Bold"><span class="Bold">Do not use naloxone hydrochloride nasal spray </span></span>if you are allergic to naloxone hydrochloride or any of the ingredients in naloxone hydrochloride nasal spray. See the end of this leaflet for a complete list of ingredients in naloxone hydrochloride nasal spray.<span class="Bold">  </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before using naloxone hydrochloride nasal spray? </span> </p> <p>Before using naloxone hydrochloride nasal spray, tell your healthcare provider about all of your medical conditions, including if you:</p> <ul class="Disc"> <li>have heart problems</li> <li>are pregnant or plan to become pregnant. Use of naloxone hydrochloride nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use naloxone hydrochloride nasal spray.</li> <li>are breastfeeding or plan to breastfeed. It is not known if naloxone hydrochloride passes into your breast milk.</li> </ul> <p> <span class="Bold">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I use naloxone hydrochloride nasal spray? </span> </p> <p> <span class="Bold">Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use naloxone hydrochloride nasal spray.</span> </p> <ul class="Disk"> <li>Use naloxone hydrochloride nasal spray exactly as prescribed by your healthcare provider.</li> <li>Each naloxone hydrochloride nasal spray contains only 1 dose of medicine and cannot be reused.</li> <li>Lay the person on their back. Support their neck with your hand and allow the head to tilt back before giving naloxone hydrochloride nasal spray. </li> <li>Naloxone hydrochloride nasal spray should be given into one nostril. </li> <li>If additional doses are needed, give naloxone hydrochloride nasal spray in the other nostril.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of naloxone hydrochloride nasal spray? </span> </p> <p> <span class="Bold">Naloxone hydrochloride nasal spray may cause serious side effects, including:</span> </p> <ul class="Disk"> <li> <span class="Bold">Sudden opioid withdrawal symptoms.</span> In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving naloxone hydrochloride nasal spray and may include:</li> </ul> <p> ○ body aches ○ sneezing ○ nervousness</p> <p> ○ diarrhea ○ goose bumps ○ restlessness or irritability </p> <p> ○ increased heart rate ○ sweating ○ shivering or trembling</p> <p> ○ fever ○ yawning ○ stomach cramping</p> <p> ○ runny nose ○ nausea or vomiting ○ weakness</p> <p> ○ increased blood pressure</p> <p>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. </p> <p>These are not all of the possible side effects of naloxone hydrochloride nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store naloxone hydrochloride nasal spray?</span> </p> <ul class="Disk"> <li>Store below 77°F (25°C).</li> <li>Excursions permitted up to 104°F (40°C).</li> <li>Do not freeze or expose to excessive heat above 104°F (40°C).</li> <li>Keep naloxone hydrochloride nasal spray in its box until ready to use. Protect from light.</li> <li>Replace naloxone hydrochloride nasal spray before the expiration date on the box.</li> </ul> <p> <span class="Bold">Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of naloxone hydrochloride nasal spray. </span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use naloxone hydrochloride nasal spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about naloxone hydrochloride nasal spray that is written for health professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in naloxone hydrochloride nasal spray?</span> </p> <p> <span class="Bold">Active ingredient:</span> naloxone hydrochloride </p> <p> <span class="Bold">Inactive ingredients:</span> benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water</p> <p>Naloxone hydrochloride nasal spray is not made with natural rubber latex.</p> <p> <span class="Bold">Teva Pharmaceuticals USA, Inc.,</span> North Wales, PA 19454</p> <p> For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872).</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">PATIENT INFORMATION</span>\n</p>\n<p>\n<span class=\"Bold\">Naloxone Hydrochloride (nal ox’ one hye” droe klor’ ide)</span>\n</p>\n<p>\n<span class=\"Bold\">Nasal Spray</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">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.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about naloxone hydrochloride nasal spray? </span>\n</p>\n<p>Naloxone hydrochloride nasal spray is used to temporarily reverse the effects of opioid medicines. The medicine in naloxone hydrochloride nasal spray has no effect in people who are not taking opioid medicines. Always carry naloxone hydrochloride nasal spray with you in case of an opioid emergency.</p>\n<p>1.  Use naloxone hydrochloride nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:</p>\n<ul class=\"Disk\">\n<li>unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the middle of their chest (sternum)</li>\n<li>breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing</li>\n<li>the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called “pinpoint pupils,” in someone difficult to awaken</li>\n</ul>\n<p>2.  Family members, caregivers, or other people who may have to use naloxone hydrochloride nasal spray in an opioid emergency should know where naloxone hydrochloride nasal spray is stored and how to give naloxone hydrochloride before an opioid emergency happens.</p>\n<p>3.  <span class=\"Bold\">Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray.</span> Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. </p>\n<p>4.  The signs and symptoms of an opioid emergency can return after naloxone hydrochloride nasal spray is given. If this happens, give another dose after 2 to 3 minutes using a new naloxone hydrochloride nasal spray and watch the person closely until emergency help is received.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is naloxone hydrochloride nasal spray?</span>\n</p>\n<ul class=\"Disc\">\n<li>Naloxone hydrochloride nasal spray is a prescription medicine used for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.</li>\n<li>Naloxone hydrochloride nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray, even if the person wakes up. </li>\n<li>Naloxone hydrochloride nasal spray is safe and effective in children for known or suspected opioid overdose.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not use naloxone hydrochloride nasal spray? </span>\n</p>\n<p>\n<span class=\"Bold\"><span class=\"Bold\">Do not use naloxone hydrochloride nasal spray </span></span>if you are allergic to naloxone hydrochloride or any of the ingredients in naloxone hydrochloride nasal spray. See the end of this leaflet for a complete list of ingredients in naloxone hydrochloride nasal spray.<span class=\"Bold\">  </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before using naloxone hydrochloride nasal spray? </span>\n</p>\n<p>Before using naloxone hydrochloride nasal spray, tell your healthcare provider about all of your medical conditions, including if you:</p>\n<ul class=\"Disc\">\n<li>have heart problems</li>\n<li>are pregnant or plan to become pregnant. Use of naloxone hydrochloride nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use naloxone hydrochloride nasal spray.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if naloxone hydrochloride passes into your breast milk.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use naloxone hydrochloride nasal spray? </span>\n</p>\n<p>\n<span class=\"Bold\">Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use naloxone hydrochloride nasal spray.</span>\n</p>\n<ul class=\"Disk\">\n<li>Use naloxone hydrochloride nasal spray exactly as prescribed by your healthcare provider.</li>\n<li>Each naloxone hydrochloride nasal spray contains only 1 dose of medicine and cannot be reused.</li>\n<li>Lay the person on their back. Support their neck with your hand and allow the head to tilt back before giving naloxone hydrochloride nasal spray. </li>\n<li>Naloxone hydrochloride nasal spray should be given into one nostril. </li>\n<li>If additional doses are needed, give naloxone hydrochloride nasal spray in the other nostril.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of naloxone hydrochloride nasal spray? </span>\n</p>\n<p>\n<span class=\"Bold\">Naloxone hydrochloride nasal spray may cause serious side effects, including:</span>\n</p>\n<ul class=\"Disk\">\n<li>\n<span class=\"Bold\">Sudden opioid withdrawal symptoms.</span> In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving naloxone hydrochloride nasal spray and may include:</li>\n</ul>\n<p> ○ body aches ○ sneezing ○ nervousness</p>\n<p> ○ diarrhea ○ goose bumps ○ restlessness or irritability </p>\n<p> ○ increased heart rate ○ sweating ○ shivering or trembling</p>\n<p> ○ fever ○ yawning ○ stomach cramping</p>\n<p> ○ runny nose ○ nausea or vomiting ○ weakness</p>\n<p> ○ increased blood pressure</p>\n<p>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. </p>\n<p>These are not all of the possible side effects of naloxone hydrochloride nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store naloxone hydrochloride nasal spray?</span>\n</p>\n<ul class=\"Disk\">\n<li>Store below 77°F (25°C).</li>\n<li>Excursions permitted up to 104°F (40°C).</li>\n<li>Do not freeze or expose to excessive heat above 104°F (40°C).</li>\n<li>Keep naloxone hydrochloride nasal spray in its box until ready to use. Protect from light.</li>\n<li>Replace naloxone hydrochloride nasal spray before the expiration date on the box.</li>\n</ul>\n<p>\n<span class=\"Bold\">Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of naloxone hydrochloride nasal spray. </span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use naloxone hydrochloride nasal spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about naloxone hydrochloride nasal spray that is written for health professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in naloxone hydrochloride nasal spray?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> naloxone hydrochloride </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water</p>\n<p>Naloxone hydrochloride nasal spray is not made with natural rubber latex.</p>\n<p>\n<span class=\"Bold\">Teva Pharmaceuticals USA, Inc.,</span> North Wales, PA 19454</p>\n<p> For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872).</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.                                                                                Rev. A 3/2022

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INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

Naloxone Hydrochloride (nal ox’ one hye” droe klor’ ide)

{ "type": "p", "children": [], "text": "\nNaloxone Hydrochloride (nal ox’ one hye” droe klor’ ide)\n" }

Nasal Spray

{ "type": "p", "children": [], "text": "\nNasal Spray\n" }

You and your family members or caregivers should read the Instructions for Use that comes with naloxone hydrochloride 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 naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "You and your family members or caregivers should read the Instructions for Use that comes with naloxone hydrochloride 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 naloxone hydrochloride nasal spray." }

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

{ "type": "p", "children": [], "text": "\nUse naloxone hydrochloride nasal spray for known or suspected opioid overdose in adults and children.\n" }

Important: For use in the nose only.

{ "type": "p", "children": [], "text": "\nImportant: For use in the nose only.\n" }

{ "type": "ul", "children": [ "\nDo not remove or test the naloxone hydrochloride nasal spray until ready to use.\n", "\nEach naloxone hydrochloride nasal spray has 1 dose and cannot be reused.\n", "\nYou do not need to prime naloxone hydrochloride nasal spray.\n" ], "text": "" }

How to use naloxone hydrochloride nasal spray:

{ "type": "p", "children": [], "text": "\nHow to use naloxone hydrochloride nasal spray:\n" }

Step 1. Lay the person on their back to receive a dose of naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nStep 1. Lay the person on their back to receive a dose of naloxone hydrochloride nasal spray." }

Step 2. Remove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nStep 2. Remove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray." }

Note: Naloxone hydrochloride 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 naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen.

{ "type": "p", "children": [], "text": "\nNote: Naloxone hydrochloride 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 naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen." }

Step 3. Hold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.

{ "type": "p", "children": [], "text": "\nStep 3. Hold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle." }

Step 4. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person’s nose.

{ "type": "p", "children": [], "text": "\nStep 4. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person’s nose." }

Step 5. Press the plunger firmly to give the dose of naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nStep 5. Press the plunger firmly to give the dose of naloxone hydrochloride nasal spray." }

Step 6. Remove the naloxone hydrochloride nasal spray from the nostril after giving the dose.

{ "type": "p", "children": [], "text": "\nStep 6. Remove the naloxone hydrochloride nasal spray from the nostril after giving the dose." }

What to do after naloxone hydrochloride nasal spray has been used:

{ "type": "p", "children": [], "text": "\nWhat to do after naloxone hydrochloride nasal spray has been used:\n" }

Step 7. Get emergency medical help right away.

{ "type": "p", "children": [], "text": "\nStep 7. Get emergency medical help right away.\n" }

{ "type": "ul", "children": [ "Move the person on their side (recovery position) after giving naloxone hydrochloride nasal spray." ], "text": "" }

{ "type": "ul", "children": [ "Watch the person closely.", "If the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Naloxone hydrochloride nasal spray may be dosed every 2 to 3 minutes, if available.", "Repeat Steps 2 through 6 using a new naloxone hydrochloride nasal spray to give another dose in the other nostril. If additional naloxone hydrochloride nasal sprays are available, Steps 2 through 6 may be repeated every 2 to 3 minutes until the person responds or emergency medical help is received." ], "text": "" }

Step 8. Put the used naloxone hydrochloride nasal spray back into its box.

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Step 9. Throw away (dispose of) the used naloxone hydrochloride nasal spray in a place that is away from children.

{ "type": "p", "children": [], "text": "\nStep 9. Throw away (dispose of) the used naloxone hydrochloride nasal spray in a place that is away from children." }

How should I store naloxone hydrochloride nasal spray?

{ "type": "p", "children": [], "text": "\nHow should I store naloxone hydrochloride nasal spray?\n" }

{ "type": "ul", "children": [ "Store below 77°F (25°C).", "Excursions permitted up to 104°F (40°C).", "Do not freeze or expose to excessive heat above 104°F (40°C).", "Keep naloxone hydrochloride nasal spray in the box until ready to use. Protect from light.", "Replace naloxone hydrochloride nasal spray before the expiration date on the box." ], "text": "" }

Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep naloxone hydrochloride nasal spray and all medicines out of the reach of children. \n" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872).

{ "type": "p", "children": [], "text": "For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872)." }

Teva Pharmaceuticals USA, Inc. North Wales, PA 19454

{ "type": "p", "children": [], "text": "\nTeva Pharmaceuticals USA, Inc.\nNorth Wales, PA 19454" }

Rev. A 3/2022

{ "type": "p", "children": [], "text": "Rev. A 3/2022" }

Naloxone Hydrochloride Nasal Spray

{ "type": "p", "children": [], "text": "\nNaloxone Hydrochloride Nasal Spray\n" }

QUICK START GUIDE

{ "type": "p", "children": [], "text": "\nQUICK START GUIDE\n" }

Opioid Overdose Response Instructions

{ "type": "p", "children": [], "text": "\nOpioid Overdose Response Instructions\n" }

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

{ "type": "p", "children": [], "text": "\nUse naloxone hydrochloride nasal spray for known or suspected opioid overdose in adults and children. \n" }

Important: For use in the nose only.

{ "type": "p", "children": [], "text": "\nImportant: For use in the nose only. \n" }

Do not remove or test the naloxone hydrochloride nasal spray until ready to use.

{ "type": "p", "children": [], "text": "\nDo not remove or test the naloxone hydrochloride nasal spray until ready to use.\n" }

1 Identify Opioid Overdose and Check for Response

{ "type": "p", "children": [], "text": "\n1 Identify Opioid Overdose and Check for Response\n" }

Ask person if he or she is okay and shout name.

{ "type": "p", "children": [], "text": "\nAsk person if he or she is okay and shout name." }

Shake shoulders and firmly rub the middle of their chest.

{ "type": "p", "children": [], "text": "\nShake shoulders and firmly rub the middle of their chest." }

Check for signs of opioid overdose:

{ "type": "p", "children": [], "text": "\nCheck for signs of opioid overdose:\n" }

{ "type": "ul", "children": [ "Will not wake up or respond to your voice or touch", "Breathing is very slow, irregular, or has stopped", "Center part of their eye is very small, sometimes called “pinpoint pupils”" ], "text": "" }

Lay the person on their back to receive a dose of naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nLay the person on their back to receive a dose of naloxone hydrochloride nasal spray. \n" }

2 Give naloxone hydrochloride nasal spray

{ "type": "p", "children": [], "text": "\n2 Give naloxone hydrochloride nasal spray\n" }

Remove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nRemove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray." }

Note: Naloxone hydrochloride 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 naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen.

{ "type": "p", "children": [], "text": "\nNote: Naloxone hydrochloride 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 naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen." }

Hold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.

{ "type": "p", "children": [], "text": "\nHold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle." }

Gently insert the tip of the nozzle into either nostril.

{ "type": "p", "children": [], "text": "\nGently insert the tip of the nozzle into either nostril.\n" }

{ "type": "ul", "children": [ "Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril, until your fingers on either side of the nozzle are against the bottom of the person’s nose." ], "text": "" }

Press the plunger firmly to give the dose of naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nPress the plunger firmly to give the dose of naloxone hydrochloride nasal spray." }

{ "type": "ul", "children": [ "Remove the naloxone hydrochloride nasal spray from the nostril after giving the dose." ], "text": "" }

3 Call for emergency medical help, Evaluate, and Support

{ "type": "p", "children": [], "text": "\n3 Call for emergency medical help, Evaluate, and Support\n" }

Get emergency medical help right away.

{ "type": "p", "children": [], "text": "\nGet emergency medical help right away.\n" }

Move the person on their side (recovery position) after giving naloxone hydrochloride nasal spray.

{ "type": "p", "children": [], "text": "\nMove the person on their side (recovery position) after giving naloxone hydrochloride nasal spray." }

Watch the person closely.

{ "type": "p", "children": [], "text": "\nWatch the person closely.\n" }

If the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Naloxone hydrochloride nasal spray may be dosed every 2 to 3 minutes, if available.

{ "type": "p", "children": [], "text": "\nIf the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Naloxone hydrochloride nasal spray may be dosed every 2 to 3 minutes, if available." }

Repeat Step 2 using a new naloxone hydrochloride nasal spray to give another dose in the other nostril. If additional naloxone hydrochloride nasal sprays are available, repeat step 2 every 2 to 3 minutes until the person responds or emergency medical help is received.

{ "type": "p", "children": [], "text": "\nRepeat Step 2 using a new naloxone hydrochloride nasal spray to give another dose in the other nostril. If additional naloxone hydrochloride nasal sprays are available, repeat step 2 every 2 to 3 minutes until the person responds or emergency medical help is received." }

For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "\nFor more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.\n" }

Teva Pharmaceuticals USA, Inc. North Wales, PA 19454

{ "type": "p", "children": [], "text": "\nTeva Pharmaceuticals USA, Inc.\nNorth Wales, PA 19454" }

Rev. A 3/2022

{ "type": "p", "children": [], "text": "Rev. A 3/2022" }

NDC 0591-2971-99 0.1 mL intranasal spray per unit For use in the nose only Rx only

{ "type": "p", "children": [], "text": "NDC 0591-2971-99\n0.1 mL intranasal spray per unit\nFor use in the nose only\nRx only" }

Naloxone Hydrochloride Nasal Spray 4 mg

{ "type": "p", "children": [], "text": "Naloxone Hydrochloride Nasal Spray\n4 mg" }

Use Naloxone Hydrochloride Nasal Spray for known or suspected opioid overdose in adults and children.

{ "type": "p", "children": [], "text": "Use Naloxone Hydrochloride Nasal Spray for known or\nsuspected opioid overdose in adults and children." }

Important: For use in the nose only.

{ "type": "p", "children": [], "text": "Important: For use in the nose only." }

Do not remove or test the Naloxone Hydrochloride  Nasal Spray until ready to use.

{ "type": "p", "children": [], "text": "Do not remove or test the Naloxone Hydrochloride \nNasal Spray until ready to use." }

This box contains two (2) 4 mg doses of naloxone HCl,  USP in 0.1 mL of nasal spray.

{ "type": "p", "children": [], "text": "This box contains two (2) 4 mg doses of naloxone HCl, \nUSP in 0.1 mL of nasal spray." }

Two Pack

{ "type": "p", "children": [], "text": "Two Pack" }

CHECK PRODUCT EXPIRATION DATE BEFORE USE.

{ "type": "p", "children": [], "text": "CHECK PRODUCT EXPIRATION DATE BEFORE USE." }

ZIMHI is indicated in adults and pediatric patients for:

{ "type": "p", "children": [], "text": "ZIMHI is indicated in adults and pediatric patients for:" }

{ "type": "ul", "children": [ "the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression." ], "text": "" }

ZIMHI is intended for immediate administration as emergency therapy in settings where opioids may be present.

{ "type": "p", "children": [], "text": "ZIMHI is intended for immediate administration as emergency therapy in settings where opioids may be present." }

ZIMHI is not a substitute for emergency medical care.

{ "type": "p", "children": [], "text": "ZIMHI is not a substitute for emergency medical care." }

ZIMHI is for intramuscular and subcutaneous use only.

Because treatment of known or 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 ZIMHI and the Instructions for Use.

ZIMHI is intended to be administered by individuals 12 years of age or older.Younger individuals or those with limited hand strength may find the device difficult to use.

ZIMHI is light sensitive. Store ZIMHI in the outer case provided to protect it from light.

Prior to a medical emergency (during storage), periodically visually inspect ZIMHI through the viewing window on the device. If the solution is discolored yellow or brown color, cloudy, or contains particles, replace ZIMHI with a new one [ see How Supplied/Storage and Handling (16.2)].

Do not attempt to reuse ZIMHI. Each ZIMHI contains a single-dose of naloxone hydrochloride for single-dose injection.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for ZIMHI ®. Emphasize the following instructions to the patient or caregiver:

- Immediately after injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the safety guard.

- Never put thumb, fingers,or hand over the exposed needle. Failure to follow these instructions may result in a needlestick injury.  If an accidental needlestick occurs, get medical help immediately [ see Warnings and Precautions (5.4)]. - Do NOT attempt to re-cap the needle with the needle cap once it has been removed [ see Warnings and Precautions (5.4)]. - Place the patient in the lateral recumbent position (recovery position). - ZIMHI must be used and/or properly disposed of as described below once the protective cap covering the needle is removed.  - Put the used syringe into the blue case, close the case, and give your used ZIMHI syringe to the healthcare provider for inspection and proper disposal. - Tell the healthcare provider that you have received or administered an injection of naloxone HCl. Show the healthcare provider where the injection was administered.

Initial Dosing

Administer the initial dose of ZIMHI ®to adult or pediatric patients intramuscularly or subcutaneously into the anterolateral aspect of the thigh, through clothing if necessary, and seek emergency medical assistance. Administer ZIMHI ®as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death.

Repeat Dosing

The requirement for repeat doses of ZIMHI depends upon the amount, type, and route of administration of the opioid being antagonized.

If the desired response is not obtained after 2 or 3 minutes, an additional dose of ZIMHI may be administered. If there is still no response and additional doses are available, additional doses of ZIMHI may be administered every 2 to 3 minutes until emergency medical assistance arrives.

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

If the patient responds to ZIMHI and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of ZIMHI and continue surveillance of the patient after administering an additional dose.

Reversal of respiratory depression 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 ZIMHI.

Dosing in Adults and Pediatric Patients

Instruct patients or their caregivers to administer ZIMHI according to the Instructions for Use, intramuscularly or subcutaneously.

Dosing in Pediatric Patients under Age One Year

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering ZIMHI. Carefully observe the administration site for signs of infection following resolution of the opioid emergency.

Injection: 5 mg/0.5 mL naloxone hydrochloride is a clear, colorless to slightly yellow, sterile solution in a single-dose, pre-filled syringe. Each ZIMHI 5 mg delivers 5 mg naloxone hydrochloride (equivalent to 4.5 mg naloxone) injection, USP (0.5 mL).

{ "type": "p", "children": [], "text": "Injection: 5 mg/0.5 mL naloxone hydrochloride is a clear, colorless to slightly yellow, sterile solution in a single-dose, pre-filled syringe. Each ZIMHI 5 mg delivers 5 mg naloxone hydrochloride (equivalent to 4.5 mg naloxone) injection, USP (0.5 mL)." }

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

{ "type": "p", "children": [], "text": "ZIMHI is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients." }

The duration of action of most opioids may exceed that of ZIMHI 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 delivering the first dose of ZIMHI. Keep the patient under continued surveillance and administer additional doses of ZIMHI 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.

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)]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

The use of ZIMHI in patients who are opioid dependent results in opioid withdrawal characterized by rapid onset of severe body aches, vomiting, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, 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 patients 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. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, 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 product which can be titrated to effect and, where applicable, dosed according to weight [ see Use in Specific Populations (8.4)].

After use, the ZIMHI needle is exposed until the safety guard is deployed. A needlestick injury could occur during use in emergency situations. In the event that an accidental needlestick occurs, medical attention should be sought. Potential exposure to blood borne pathogens including HIV, HBV, and HCV requires immediate evaluation by a medical professional. Stress to patients the importance of familiarizing themselves with the device and its operation prior to experiencing an emergency situation, so they are familiar with the safety guard and its deployment.

The following serious adverse reactions are discussed elsewhere in the labeling:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are discussed elsewhere in the labeling:" }

{ "type": "ul", "children": [ "Precipitation of Severe Opioid Withdrawal [\n \n see Warnings and Precautions (5.3)]\n \n " ], "text": "" }

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.

{ "type": "p", "children": [], "text": "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." }

The following adverse reactions were observed in ZIMHI clinical studies in healthy volunteers without opioid dependence: nausea, dizziness, lightheadedness, and elevated bilirubin.

{ "type": "p", "children": [], "text": "The following adverse reactions were observed in ZIMHI clinical studies in healthy volunteers without opioid dependence: nausea, dizziness, lightheadedness, and elevated bilirubin." }

The following adverse reactions have been identified during post-approval use of naloxone hydrochloride in the post-operative 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 post-operative patients have resulted in significant reversal of analgesia and have caused agitation [ see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "The following adverse reactions have been identified during post-approval use of naloxone hydrochloride in the post-operative 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 post-operative patients have resulted in significant reversal of analgesia and have caused agitation [\n \n see Warnings and Precautions (5.3)].\n\n " }

Other events that have been reported in post-marketing use of naloxone hydrochloride include agitation, disorientation, confusion, and anger.

{ "type": "p", "children": [], "text": "Other events that have been reported in post-marketing use of naloxone hydrochloride include agitation, disorientation, confusion, and anger." }

Abrupt reversal of opioid effects in persons who were opioid dependent resulted in opioid withdrawal characterized by rapid onset of severe body aches, vomiting, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In some patients, aggressive behavior has occurred in the context of 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)].

{ "type": "p", "children": [], "text": "Abrupt reversal of opioid effects in persons who were opioid dependent resulted in opioid withdrawal characterized by rapid onset of severe body aches, vomiting, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In some patients, aggressive behavior has occurred in the context of abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal signs and symptoms also included: convulsions, excessive crying, and hyperactive reflexes [\n \n see Warnings and Precautions (5.3)].\n\n " }

Risk Summary

Life-sustaining therapy for opioid overdose should not be withheld ( seeClinical Considerations). Available data from retrospective cohort studies on naloxone use in pregnant women have not identified a drug-associated risk of major birth defects or miscarriage. 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 4-times and 8-times, respectively, a human dose of 10 mg/day.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

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 ZIMHI for opioid overdose should not be withheld because of potential concerns regarding the effects of ZIMHI on the fetus.

Data

Animal Data

Naloxone hydrochloride was administered during organogenesis to mice and rats at doses 4-times and 8-times, respectively, the dose of 10 mg/day given to a 50 kg human (when based on body surface area or mg/m 2). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

Risk Summary

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

The safety and effectiveness of ZIMHI ®(for intramuscular and subcutaneous use) have been established in pediatric patients of all ages for the emergency treatment of 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 another naloxone hydrochloride injectable product. No pediatric studies were conducted for ZIMHI.

Absorption of naloxone hydrochloride following subcutaneous or intramuscular administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized.

In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. Unlike acute opioid withdrawal in adults, acute opioid withdrawal in neonates manifesting as seizures may be life-threatening if not recognized and properly treated. Other signs and symptoms in neonates may include excessive crying and hyperactive reflexes. In these settings where it may be preferable to avoid the abrupt precipitation of acute opioid withdrawal symptoms, consider use of an alternative, naloxone hydrochloride product that can be dosed according to weight and titrated to effect. [ see Warnings and Precautions (5.3)].

In pediatric patients under the age of one year, the caregiver should pinch the thigh muscle while administering ZIMHI. Carefully observe the administration site for evidence of residual needle parts, signs of infection, or both. [ see Dosing Information (2.2)].

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 can be higher in these patients.

Clinical studies of naloxone hydrochloride 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.

ZIMHI (naloxone hydrochloride injection, USP) is an opioid antagonist supplied in a single-dose pre-filled syringe. ZIMHI is not made with natural rubber latex. Chemically, naloxone hydrochloride is the hydrochloride salt of 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride with the following structure:

{ "type": "p", "children": [], "text": "ZIMHI (naloxone hydrochloride injection, USP) is an opioid antagonist supplied in a single-dose pre-filled syringe. ZIMHI is not made with natural rubber latex. Chemically, naloxone hydrochloride is the hydrochloride salt of 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride with the following structure:" }

C 19H 21NO 4• HCl

{ "type": "p", "children": [], "text": "C\n \n 19H\n \n 21NO\n \n 4• HCl\n\n " }

399.9 g/mol

{ "type": "p", "children": [], "text": "399.9 g/mol" }

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

{ "type": "p", "children": [], "text": "Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform." }

Each 0.5 mL contains 5 mg naloxone hydrochloride (equivalent to 4.5 mg naloxone), 4.17 mg sodium chloride, hydrochloric acid to adjust pH, and water for injection.

{ "type": "p", "children": [], "text": "Each 0.5 mL contains 5 mg naloxone hydrochloride (equivalent to 4.5 mg naloxone), 4.17 mg sodium chloride, hydrochloric acid to adjust pH, and water for injection." }

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. Also, it can 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 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.

In a pharmacokinetic study of 14 healthy adults, a single intramuscular injection of 5 mg ZIMHI in a single-dose pre-filled syringe in a delivery device provides significantly higher C maxand AUC compared to a single intramuscular injection of 2 mg naloxone hydrochloride (1mg /1mL). Naloxone plasma concentration versus time profiles are shown in Figure 1.

The pharmacokinetic parameters of naloxone in plasma are shown in Table 1.

Table 1: Mean Pharmacokinetic Parameters (CV%) for Naloxone Following a Single Intramuscular Injection of 5 mg ZIMHI®(naloxone HCl) anda SingleIntramuscular Injection of 2 mg Naloxone HCl in Healthy Subjects

<div class="scrollingtable"><table> <col width="148"/> <col width="269"/> <col width="318"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule Toprule">Parameter</td><td align="center" class="Lrule Rrule Toprule">Intramuscular Injection of 5 mg ZIMHI <br/> (N = 14) </td><td align="center" class="Lrule Rrule Toprule">Intramuscular Injection of 2 mg Naloxone HCl <br/> (N = 14) </td> </tr> <tr> <td class="Lrule Rrule Toprule">T <span class="Sub">max</span>(h)* </td><td align="center" class="Lrule Rrule Toprule">0.25 (0.17, 0.52)</td><td align="center" class="Lrule Rrule Toprule">0.25 (0.05, 3.00)</td> </tr> <tr> <td class="Lrule Rrule Toprule">C <span class="Sub">max</span>(ng/mL) </td><td align="center" class="Lrule Rrule Toprule">17.2 (44)</td><td align="center" class="Lrule Rrule Toprule">3.58 (58.1)</td> </tr> <tr> <td class="Lrule Rrule Toprule">AUC <span class="Sub">0-t</span>(ng.h/mL) </td><td align="center" class="Lrule Rrule Toprule">26.2 (21.5)</td><td align="center" class="Lrule Rrule Toprule">9.43 (23.8)</td> </tr> <tr> <td class="Lrule Rrule Toprule">AUC <span class="Sub">0-inf</span>(ng.h/mL) </td><td align="center" class="Lrule Rrule Toprule">26.6 (21.2)</td><td align="center" class="Lrule Rrule Toprule">9.97 (22.6)</td> </tr> <tr> <td class="Lrule Rrule Toprule">AUC <span class="Sub">0-0.04h</span>(ng.h/mL) </td><td align="center" class="Lrule Rrule Toprule">0.02 (208)</td><td align="center" class="Lrule Rrule Toprule">0.01 (164)</td> </tr> <tr> <td class="Lrule Rrule Toprule">AUC <span class="Sub">0-0.08h</span>(ng.h/mL) </td><td align="center" class="Lrule Rrule Toprule">0.15 (117)</td><td align="center" class="Lrule Rrule Toprule">0.04 (128)</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">T <span class="Sub">1/2</span>(h) </td><td align="center" class="Lrule Rrule Toprule">1.50 (15.2)</td><td align="center" class="Lrule Rrule Toprule">1.86 (28.9)</td> </tr> </tbody> </table></div>

*t maxreported as median (minimum, maximum)

Figure 1Mean ± SD Plasma Concentration of Naloxone, (a) 0-30 minand (b) 0-12 h Following a Single Intramuscular Administration of 5 mg ZIMHIand a Single Intramuscular Administration of 2 mg Naloxone HCl

a)

b)

Distribution Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

Elimination Following a single 5 mg/0.5 mL mg ZIMHI injection, the mean plasma half-life of naloxone in healthy adults was 1.50 hours with values for individual subjects ranging from 1.18 to 1.87 hours. In a neonatal study of naloxone injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.

Metabolism  Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major metabolite.

Excretion  After an oral or intravenous dose, about 25-40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

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 4-times and 8-times, respectively, the dose of 10 mg/day given to a 50 kg human (when based on surface area or mg/m 2), demonstrated no adverse effect of naloxone hydrochloride on fertility.

ZIMHI (naloxone hydrochloride injection, USP) 5 mg/0.5 mL is a clear, colorless to slightly yellow, sterile solution provided as follows:

NDC 84571-140-11:Carton containing one case which contains one 5 mg/0.5 mL single-dose, pre-filled syringe

NDC 84571-140-02: Carton containing two cases, each of which contain one 5 mg/0.5 mL single-dose, pre-filled syringe per case  

NDC 84571-140-11: Case containing one 5 mg/0.5 mL single-dose, pre-filled syringe

Store ZIMHI in the outer case provided.

Store below 77 oF (25 oC). Excursions permitted up to 104 oF (40 oC).  Do Notfreeze or expose to excessive heat above 104 oF (40 oC). Protect from light.

Prior to a medical emergency (during storage), periodically visually inspect ZIMHI through the viewing window on the device. If the solution is discolored yellow or brown color, cloudy, or contains particles, replace ZIMHI with a new one.

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

{ "type": "p", "children": [], "text": "Advise the patient and family members or caregivers to read the FDA-approved patient labeling (\n \n Patient Informationand\n \n Instructions for Use).\n\n " }

Instruct patients and their family members or caregivers to become familiar with all information contained in the case and carton as soon as they receive ZIMHI.

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers to become familiar with all information contained in the case and carton as soon as they receive ZIMHI." }

Inform patients of the following:

{ "type": "p", "children": [], "text": "Inform patients of the following:" }

{ "type": "ul", "children": [ "ZIMHI is for the emergency treatment of known or suspected overdose. \n \n", "It is administered by a caregiver according to the Instructions for Use. \n \n", "After administration, the caregiver should get emergency help immediately." ], "text": "" }

Recognition of Opioid Overdose

{ "type": "p", "children": [], "text": "\nRecognition of Opioid Overdose\n" }

Instruct the patients and their family members or caregivers how to recognize the signs and symptoms of an opioid overdose requiring the use of ZIMHI ®such as the following:

{ "type": "p", "children": [], "text": "Instruct the patients and their family members or caregivers how to recognize the signs and symptoms of an opioid overdose requiring the use of ZIMHI\n \n ®such as the following:\n\n " }

{ "type": "ul", "children": [ "Extreme somnolence - inability to awaken a patient verbally or upon a firm sternal rub. \n \n", "Respiratory depression - this can range from slow or shallow respiration to no respiration in a patient who is unarousable. \n \n", "Other signs and symptoms that may accompany somnolence and respiratory depression include the following:\n \n \nMiosis. \n \n\nBradycardia and/or hypotension.\n\n" ], "text": "" }

Risk of Recurrent Respiratory and Central Nervous System Depression

{ "type": "p", "children": [], "text": "\nRisk of Recurrent Respiratory and Central Nervous System Depression\n" }

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

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers that, because the duration of action of most opioids may exceed that of ZIMHI, they must seek immediate emergency medical assistance after the first dose of ZIMHI and keep the patient under continued surveillance [\n \n see Dosage and Administration (2.2),\n \n Warnings and Precautions (5.3)].\n\n " }

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

{ "type": "p", "children": [], "text": "\nLimited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists\n" }

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 ZIMHI [ see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "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 ZIMHI [\n \n see Dosage and Administration (2.2), Warnings and Precautions (5.3)].\n\n " }

Precipitation of Severe Opioid Withdrawal

{ "type": "p", "children": [], "text": "\nPrecipitation of Severe Opioid Withdrawal\n" }

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

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers that the use of ZIMHI in patients who are opioid dependent may precipitate an acute abstinence syndrome 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 [\n \n see Warnings and Precautions (5.3), Adverse Reactions (6)].\n\n " }

Administration Instructions

{ "type": "p", "children": [], "text": "\nAdministration Instructions\n" }

Instruct patients and their family members or caregivers to carefully read the Instructions for Use before an emergency arises. Emphasize the following important information:

{ "type": "p", "children": [], "text": "Instruct patients and their family members or caregivers to carefully read the Instructions for Use before an emergency arises. Emphasize the following important information:" }

{ "type": "ul", "children": [ "\nZIMHI is intended to be administered by individuals 12 years of age or older.Younger individuals or those with limited hand strength may find the device difficult to use.  \n \n", "Each syringe is for a single-dose injection. \n \n", "Make sure ZIMHI is present whenever persons may be intentionally or accidentally exposed to an opioid to treat serious opioid overdose (i.e., opioid emergencies). \n \n", "Administer ZIMHI 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. ZIMHI is not a substitute for emergency medical care [\n \n see Dosage and Administration (2.1)]. \n \n", "When removing the needle cap, there may be a drop of liquid on the needle: this is normal. The device contains an excess of liquid to ensure the required dose is delivered. \n \n", "Place the patient in the supine position. \n \n", "Inject ZIMHI into the anterolateral aspect of the thigh (through clothing, if necessary). Instruct patients to the correct location for injection. \n \n", "Immediately after injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the Safety guard. Put the used syringe into the blue case and close the case. \n \n", "\nSeekemergencymedical careimmediatelyfollowing administration of ZIMHI. \n \n", "Place the patient in the lateral recumbent position (recovery position) as shown in the Instructions for Use. \n \n", "Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. \n \n", "Administer additional doses of ZIMHI every two to three minutes if the patient does not respond or relapses back into respiratory depression before emergency assistance arrives. \n \n", "If an accidental needlestick occurs seek medical attention immediately. Potential exposure to blood borne pathogens including HIV, HBV, and HCV requires immediate evaluation by a medical professional at an emergency room, urgent care, or your primary care provider. In addition, report accidental needle injury or device malfunction to ZMI Pharma Pharmacovigilance at (800) 230-3935. \n \n", "Complete patient information, including dosage, directions for proper administration, and precautions can be found inside each ZIMHI case or carton. A printed label on the surface of the ZIMHI case or carton shows instructions for use. \n \n", "During storage, periodically visually inspect the naloxone solution through the viewing window. If the solution is discolored yellow or brown color, cloudy or contains particles, replace ZIMHI with a new one. \n \n", "Replace ZIMHI before its expiration date." ], "text": "" }

Manufactured for ZMI Pharma, Carlsbad,, CA 92008, USA.

{ "type": "p", "children": [], "text": "Manufactured for ZMI Pharma, Carlsbad,, CA 92008, USA." }

Distributed By FFF Enterprises Corp., 44000 Winchester Road, Temecula, CA 92590.

{ "type": "p", "children": [], "text": "Distributed By FFF Enterprises Corp., 44000 Winchester Road, Temecula, CA 92590." }

PATIENT PACKAGE INSERT

{ "type": "p", "children": [], "text": "\nPATIENT PACKAGE INSERT\n" }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration." }

PATIENT INFORMATION

{ "type": "p", "children": [], "text": "\nPATIENT INFORMATION\n" }

ZIMHI ® ( ZIM-hye) (naloxone hydrochloride injection, USP) Prefilled syringe for Intramuscular or Subcutaneous Use

{ "type": "p", "children": [], "text": "ZIMHI\n \n ® (\n \n ZIM-hye) \n (naloxone hydrochloride injection, USP) \n Prefilled syringe \n for Intramuscular or Subcutaneous Use\n\n " }

You and your 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.

{ "type": "p", "children": [], "text": "You and your 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 aboutZIMHI?ZIMHI is used to temporarily reverse the effects of opioid medicines. The medicine in ZIMHI has no effect in people who are not taking opioid medicines. Always carry ZIMHI with you in case of an opioid emergency.

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know aboutZIMHI?ZIMHI is used to temporarily reverse the effects of opioid medicines. The medicine in ZIMHI has no effect in people who are not taking opioid medicines. Always carry ZIMHI with you in case of an opioid emergency.\n\n " }

{ "type": "ul", "children": [ "Use ZIMHI right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:\n \n \nunusual sleepiness and you are not able to awaken the person with a loud voice or rubbing firmly on the middle of their chest (sternum) \n \n\nbreathing problems including slow or shallow breathing in someone difficult to awaken or they look like they are not breathing \n \n\nthe black circle in the center of the colored part of the eye (pupil) is very small, sometimes called “pinpoint pupils” in someone difficult to awaken\n\n\n", "Family members, caregivers, or other people who may have to use ZIMHI in an opioid emergency should know where ZIMHI is stored and how to give ZIMHI before an opioid emergency happens. Make sure everyone reads the information contained in the case and carton as soon as you receive ZIMHI. \n \n", "ZIMHI is intended to be given by people 12 years of age or older. Younger children or those with limited hand strength may find the Pre-filled syringe difficult to use. \n \n", "\nGet emergency medical help right away after using the first dose of ZIMHI. Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. \n \n", "The signs and symptoms of an opioid emergency can return after ZIMHI is given. If this happens, give additional injections using a new ZIMHI pre-filled syringe every 2 to 3 minutes and watch the person closely until emergency help is received. \n \n", "ZIMHI is a prescription medicine used in adults and children for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond. \n \n", "ZIMHI is to be given right away by a caregiver and does not take the place of emergency medical care. Get emergency medical help right away after the first dose of ZIMHI, even if the person wakes up. \n \n", "ZIMHI is safe and effective in children for known or suspected opioid overdose. \n \n", "have heart problems \n \n", "are pregnant or plan to become pregnant. Use of ZIMHI may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use ZIMHI. \n \n", "are breastfeeding or plan to breastfeed. It is not known if ZIMHI passes into your breast milk." ], "text": "" }

What isZIMHI?

{ "type": "p", "children": [], "text": "\nWhat isZIMHI?\n" }

Who should not useZIMHI?

{ "type": "p", "children": [], "text": "\nWho should not useZIMHI?\n" }

Do not use ZIMHI if you are allergic to naloxone hydrochloride or any of the ingredients in ZIMHI. See the end of this leaflet for a complete list of ingredients in ZIMHI.

{ "type": "p", "children": [], "text": "Do not use ZIMHI if you are allergic to naloxone hydrochloride or any of the ingredients in ZIMHI. See the end of this leaflet for a complete list of ingredients in ZIMHI." }

What should I tell my healthcare provider before usingZIMHI?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before usingZIMHI?\n" }

Before using ZIMHI, tell your healthcare provider about all of your medical conditions, including if you:

{ "type": "p", "children": [], "text": "Before using ZIMHI, 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.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n\n " }

How should I useZIMHI?

{ "type": "p", "children": [], "text": "\nHow should I useZIMHI?\n" }

Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use ZIMHI.

{ "type": "p", "children": [], "text": "\nRead the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use ZIMHI.\n\n " }

{ "type": "ul", "children": [ "Use ZIMHI exactly as prescribed by your healthcare provider. \n \n", "Each ZIMHI Pre-filled syringe contains only 1 dose of medicine and cannot be reused. \n \n", "ZIMHI should be injected into the muscle (intramuscular) or underneath the skin (subcutaneous) of the outer thigh. It can be injected through your clothing if needed. \n \n", "Caregivers should pinch the thigh muscle while injecting ZIMHI into a child under the age of 1 year old. \n \n", "When removing the needle cap there may be a drop of liquid on the needle: this is normal. The device contains an excess of liquid to ensure the required dose is delivered. \n \n", "\nIf an accidental needlestick injury occurs, get emergencymedical help right away.Accidental needlestick injuries may put you at risk for blood borne diseases (such as HIV, HBV, and HCV) that can cause illness or death. In addition, report an accidental needlestick injury or problems with the ZIMHI Pre-filled syringe to ZMI Pharma Pharmacovigilance at (800) 230-3935.\n \n " ], "text": "" }

What are the possible side effects ofZIMHI?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects ofZIMHI?\n" }

ZIMHI may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nZIMHI may cause serious side effects, including:\n" }

{ "type": "ul", "children": [ "\nSudden opioid withdrawal symptoms. In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving ZIMHI and may include:\n \n " ], "text": "" }

<div class="scrollingtable"><table> <col width="235"/> <col width="235"/> <col width="234"/> <tbody class="Headless"> <tr class="First"> <td>○ body aches</td><td>○ fever</td><td>○ sweating</td> </tr> <tr> <td>○ runny nose</td><td>○ sneezing</td><td>○ goose bumps</td> </tr> <tr> <td>○ yawning</td><td>○ weakness</td><td>○ shivering or trembling</td> </tr> <tr> <td>○ nervousness</td><td>○ restlessness or irritability</td><td>○ diarrhea</td> </tr> <tr> <td>○ nausea or vomiting</td><td>○ stomach cramping</td><td>○ increased blood pressure</td> </tr> <tr class="Last"> <td>○ increased heart rate</td><td></td><td></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<col width=\"235\"/>\n<col width=\"235\"/>\n<col width=\"234\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>○ body aches</td><td>○ fever</td><td>○ sweating</td>\n</tr>\n<tr>\n<td>○ runny nose</td><td>○ sneezing</td><td>○ goose bumps</td>\n</tr>\n<tr>\n<td>○ yawning</td><td>○ weakness</td><td>○ shivering or trembling</td>\n</tr>\n<tr>\n<td>○ nervousness</td><td>○ restlessness or irritability</td><td>○ diarrhea</td>\n</tr>\n<tr>\n<td>○ nausea or vomiting</td><td>○ stomach cramping</td><td>○ increased blood pressure</td>\n</tr>\n<tr class=\"Last\">\n<td>○ increased heart rate</td><td></td><td></td>\n</tr>\n</tbody>\n</table></div>" }

The most common side effects of ZIMHI include: nausea, dizziness, lightheadedness, and increased amounts of red blood cell breakdown products (bilirubin) in your blood.

{ "type": "p", "children": [], "text": "The most common side effects of ZIMHI include: nausea, dizziness, lightheadedness, and increased amounts of red blood cell breakdown products (bilirubin) in your blood." }

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.

{ "type": "p", "children": [], "text": "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." }

These are not all of the possible side effects of ZIMHI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "These are not all of the possible side effects of ZIMHI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I storeZIMHI?

{ "type": "p", "children": [], "text": "\nHow should I storeZIMHI?\n" }

{ "type": "ul", "children": [ "Store below 77°F (25°C). \n \n", "Excursions permitted up to 104°F (40°C). \n \n", "Do Not Freeze or expose to excessive heat above 104°F (40°C). Protect from Light. \n \n", "During storage, check ZIMHI often through the viewing window of the pre-filled syringe. The solution should be clear. If the ZIMHI solution is discolored, cloudy, or contains solid particles, replace it with a new ZIMHI. \n \n", "Your ZIMHI has an expiration date. Replace it before the expiration date." ], "text": "" }

KeepZIMHIand all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeepZIMHIand all medicines out of the reach of children.\n" }

General information about the safe and effective use ofZIMHI.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use ofZIMHI.\n" }

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZIMHI for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about ZIMHI that is written for health professionals.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ZIMHI for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about ZIMHI that is written for health professionals." }

What are the ingredients inZIMHI?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients inZIMHI?\n" }

Active ingredient:naloxone hydrochloride

{ "type": "p", "children": [], "text": "\nActive ingredient:naloxone hydrochloride\n\n " }

Inactive ingredients: sodium chloride, hydrochloric acid to adjust pH, and water for injection. 

{ "type": "p", "children": [], "text": "\nInactive ingredients: sodium chloride, hydrochloric acid to adjust pH, and water for injection. \n\n " }

ZIMHI is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "ZIMHI is not made with natural rubber latex." }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

Instructions for Use ZIMHI®  (ZIM-hye) (naloxone hydrochloride injection) Pre -filled syringe

{ "type": "p", "children": [], "text": "\nInstructions for Use\n\nZIMHI®  (ZIM-hye)\n \n \n (naloxone\n hydrochloride injection)\n Pre\n -filled syringe\n" }

Use ZIMHI for known or suspected opioid overdose in adults and children.

{ "type": "p", "children": [], "text": "\nUse ZIMHI for known or suspected opioid overdose in adults and children.\n" }

ZIMHI is intended to be administered by people 12 years of age or older.Younger children or those with limited hand strength may find the device difficult to use.

{ "type": "p", "children": [], "text": "\nZIMHI is intended to be administered by people 12 years of age or older.Younger children or those with limited hand strength may find the device difficult to use.\n\n " }

Read this Instructions for Use carefully before you use this product.

{ "type": "p", "children": [], "text": "\nRead this Instructions for Use carefully before you use this product.\n" }

Before you need to use your ZIMHI syringe make sure your healthcare provider shows you the right way to use it. Parents, caregivers, and others who may be in a position to administer ZIMHI should also understand how to use it. If you have questions, ask your healthcare provider.

{ "type": "p", "children": [], "text": "Before you need to use your ZIMHI syringe make sure your healthcare provider shows you the right way to use it. Parents, caregivers, and others who may be in a position to administer ZIMHI should also understand how to use it. If you have questions, ask your healthcare provider." }

Get Ready to Use ZIMHI

{ "type": "p", "children": [], "text": "\nGet Ready to Use ZIMHI\n" }

ZIMHI works like a standard prefilled syringe.

{ "type": "p", "children": [], "text": "ZIMHI works like a standard prefilled syringe." }

ZIMHI is injected downwards, into the middle of the outer thigh, (as shown), through clothing if needed.

{ "type": "p", "children": [], "text": "ZIMHI is injected downwards, into the middle of the outer thigh, (as shown), through clothing if needed." }

Ready to UseZIMHI 

{ "type": "p", "children": [], "text": "\nReady to UseZIMHI \n" }

Place the patient on their back.

{ "type": "p", "children": [], "text": "Place the patient on their back." }

When ready to inject, pull off cap to expose needle.

{ "type": "p", "children": [], "text": "When ready to inject, pull off cap to expose needle." }

DO NOT put finger on top of the device. 

{ "type": "p", "children": [], "text": "\nDO NOT put finger on top of the device. \n" }

In children under the age of 1 year old, pinch the thigh muscle while administering the dose.

{ "type": "p", "children": [], "text": "In children under the age of 1 year old, pinch the thigh muscle while administering the dose." }

Hold ZIMHI by finger grips only and slowly insert the needle into the thigh.

{ "type": "p", "children": [], "text": "Hold ZIMHI by finger grips only and slowly insert the needle into the thigh." }

After needle is in thigh: Push the plunger all the way down until it clicks and hold for 2 seconds.

{ "type": "p", "children": [], "text": "After needle is in thigh: Push the plunger all the way down until it clicks and hold for 2 seconds." }

After Use

{ "type": "p", "children": [], "text": "\nAfter Use\n" }

Right after the injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the safety guard. Put the used syringe into the blue case and close the case.

{ "type": "p", "children": [], "text": "Right after the injection, using one hand with fingers behind the needle, slide the safety guard over the needle. Do not use two hands to activate the safety guard. Put the used syringe into the blue case and close the case." }

Get Help

{ "type": "p", "children": [], "text": "\nGet Help\n" }

Get emergency medical help now

{ "type": "p", "children": [], "text": "\nGet emergency medical help now\n" }

Tell healthcare provider that you gave an injection of naloxone hydrochloride.

{ "type": "p", "children": [], "text": "Tell healthcare provider that you gave an injection of naloxone hydrochloride." }

Turn the patient on their side (recovery position) after giving ZIMHI.

{ "type": "p", "children": [], "text": "Turn the patient on their side (recovery position) after giving ZIMHI." }

Use second syringe if necessary 

{ "type": "p", "children": [], "text": "Use second syringe if necessary " }

You may need a second ZIMHI syringe if symptoms continue or recur.

{ "type": "p", "children": [], "text": "You may need a second ZIMHI syringe if symptoms continue or recur." }

If symptoms return after an injection with ZIMHI, an additional injection using another ZIMHI pre-filled syringe may be needed. Give additional injections using a new ZIMHI pre-filled syringe every 2 to 3 minutes and continue to closely watch the person until emergency help is received. Using ZIMHI does not take the place of emergency medical care.

{ "type": "p", "children": [], "text": "If symptoms return after an injection with ZIMHI, an additional injection using another ZIMHI pre-filled syringe may be needed. Give additional injections using a new ZIMHI pre-filled syringe every 2 to 3 minutes and continue to closely watch the person until emergency help is received. Using ZIMHI does not take the place of emergency medical care." }

After use and Disposal 

{ "type": "p", "children": [], "text": "\nAfter use and Disposal \n\n " }

{ "type": "ul", "children": [ "ZIMHI is a single-dose pre-filled syringe that delivers a fixed dose of naloxone hydrochloride. The pre-filled syringe cannot be reused. It is normal for most of the medicine to remain in the syringe after the dose has been injected. \n \n", "The correct dose has been injected if the plunger has been pushed all the way down and the solution window is at least partially blocked. \n \n", "Tell the healthcare provider that you have received or administered an injection of naloxone hydrochloride. Show the healthcare provider where the injection was administered. \n \n", "Give your used ZIMHI syringe, contained in the blue case, to the healthcare provider for inspection and proper disposal." ], "text": "" }

For more information see Patient Information sheet or ask your healthcare provider. 

{ "type": "p", "children": [], "text": "\nFor more information see Patient Information sheet or ask your healthcare provider. \n\n " }

How to Store —Keep ZIMHI in its plastic case nearby and ready for use at all times.

{ "type": "p", "children": [], "text": "How to Store\n \n —Keep ZIMHI in its plastic case nearby and ready for use at all times.\n" }

{ "type": "ul", "children": [ "Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do Not Freeze or expose to excessive heat above 104°F (40°C). \n \n", "Store the ZIMHI syringe in its closed plastic case to protect from light." ], "text": "" }

Check Your Stored ZIMHI® Often - The solution should be clear when viewed through the window on the device. If the solution is discolored (yellowish or brown color), cloudy or contains particles, replace ZIMHI with a new one.

{ "type": "p", "children": [], "text": "\nCheck Your Stored ZIMHI® Often - The solution should be clear when viewed through the window on the device. If the solution is discolored (yellowish or brown color), cloudy or contains particles, replace ZIMHI with a new one.\n\n " }

Your ZIMHI® Has an Expiration Date - Example YYYY-MM. Replace ZIMHI before the last day of expiration month. Dispose of expired ZIMHI properly by taking ZIMHI in its case to a healthcare provider or hospital emergency room.

{ "type": "p", "children": [], "text": "\nYour ZIMHI® Has an Expiration Date - Example YYYY-MM. Replace ZIMHI before the last day of expiration month. Dispose of expired ZIMHI properly by taking ZIMHI in its case to a healthcare provider or hospital emergency room.\n\n " }

For more information about ZIMHI pre-filled syringe and proper use of ZIMHI, call 1-800-230-3935 or visit  www.ZIMHI.com.

{ "type": "p", "children": [], "text": "For more information about ZIMHI pre-filled syringe and proper use of ZIMHI, call 1-800-230-3935 or visit\n \n  www.ZIMHI.com.\n" }

ZIMHI is a registered trademark of ZMI Pharma Corporation. 

{ "type": "p", "children": [], "text": "ZIMHI is a registered trademark of ZMI Pharma Corporation. " }

Manufactured for ZMI Pharma, Carlsbad, CA 92008, USA.

{ "type": "p", "children": [], "text": "Manufactured for ZMI Pharma, Carlsbad, CA 92008, USA." }

Distributed By FFF Enterprises Corp. 44000 Winchester Road, Temecula, CA 92590..

{ "type": "p", "children": [], "text": "Distributed By FFF Enterprises Corp. 44000 Winchester Road, Temecula, CA 92590.." }

This Instructions for Use has been approved by the U.S. Food and Drug Administration. 

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. " }

Revised: 08/2024

{ "type": "p", "children": [], "text": "Revised: 08/2024" }

NDC 84571- 140-02 Rx Only ZIMHI (naloxone HCL Injection, USP) 5 mg/ 0.5 mL

{ "type": "p", "children": [], "text": "NDC 84571-\n \n 140-02 \n \nRx Only\n ZIMHI \n (naloxone HCL Injection, USP) \n 5 mg/ 0.5 mL\n\n " }