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ZIMHI (naloxone hydrochloride injection, USP) is an opioid antagonist supplied in a single-dose prefilled syringe. ZIMHI is not made with natural rubber latex. Chemically, naloxone hydrochloride is the hydrochloride salt of 17-Allyl-4,5α-epoxy-3,14dihydroxymorphinan-6-one hydrochloride with the following structure:
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C19H21NO4• HCl - 363.8 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.
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.
ZIMHI™ is indicated in adults and pediatric patients for:
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.
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.
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].
Do not attempt to reuse ZIMHI. Each ZIMHI contains a single dose of naloxone hydrochloride for single-dose injection.
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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:
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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.
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.
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.
5 mg/0.5 mL naloxone hydrochloride is a clear, colorless to slightly yellow, sterile solution in a single-dose, prefilled syringe. Each ZIMHI 5 mg delivers 5 mg naloxone hydrochloride (equivalent to 4.5 mg naloxone) injection, USP (0.5 mL).
ZIMHI (naloxone hydrochloride injection, USP) 5 mg/0.5mL is a clear, colorless to slightly yellow, sterile solution provided as follows:
NDC38739-600-01: Case containing one 5 mg/0.5mL single-dose, prefilled syringe
NDC38739-600-02: Carton containing two cases, each of which contain one 5 mg/0.5 mL single-dose, prefilled syringe
Store ZIMHI in the outer case provided.
Store at controlled room temperature 20°C to 25°C (68°F to 77°F), excursions between 15° and 30° (59° and 86° F) are allowed. Do not refrigerate. Protect from light, extreme heat, and freezing.
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.
Manufactured for Adamis Pharmaceuticals, San Diego, CA 92130, USA Revised: Oct 2021
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.
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].
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, hyperactive reflexes [see WARNINGS AND PRECAUTIONS].
No Information Provided
Included as part of the "PRECAUTIONS" Section
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]. 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]. 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].
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.
Advise the patient and family members or caregivers to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).
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:
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:
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, WARNINGS AND PRECAUTIONS].
Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of ZIMHI [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
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, ADVERSE REACTIONS].
Instruct patients and their family members or caregivers to carefully read the Instructions for Use before an emergency arises. Emphasize the following important information:
Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.
Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome 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.
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/m2), demonstrated no adverse effect of naloxone hydrochloride on fertility.
Life-sustaining therapy for opioid overdose should not be withheld (see Clinical 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.
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.
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/m2). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.
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].
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].
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.
No Information Provided
ZIMHI is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients.
Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.
Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and 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 prefilled syringe in a delivery device provides significantly higher Cmax and 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) and a Single Intramuscular Injection of 2 mg Naloxone HCl in Healthy Subjects
| Parameter | Intramuscular Injection of 5 mg ZIMHI (N = 14) |
Intramuscular Injection of 2 mg Naloxone HCl (N = 14) |
| Tmax (h)* | 0.25 (0.17, 0.52) | 0.25 (0.05, 3.00) |
| Cmax (ng/mL) | 17.2 (44) | 3.58 (58.1) |
| AUC0-t (ng.h/mL) | 26.2 (21.5) | 9.43 (23.8) |
| AUC0-inf (ng.h/mL) | 26.6 (21.2) | 9.97 (22.6) |
| AUC0-0.04h (ng.h/mL) | 0.02 (208) | 0.01 (164) |
| AUC0-0.08h (ng.h/mL) | 0.15 (117) | 0.04 (128) |
| T1/2 (h) | 1.50 (15.2) | 1.86 (28.9) |
| *tmax reported as median (minimum, maximum) | ||
Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0-30 min and (b) 0-12 h Following a Single Intramuscular Administration of 5 mg ZIMHI and a Single Intramuscular Administration of 2 mg Naloxone HCl
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(b)
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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.
Following a single intramuscular injection of 5 mg ZIMHI, the mean plasma half-life of naloxone in healthy adults was 1.50 (15.2% CV) 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.
ZIMHI™
(ZIM-hye)
(naloxone hydrochloride injection)
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 about ZIMHI?
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.
What is ZIMHI?
Who should not use ZIMHI?
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 using ZIMHI?
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.
How should I use ZIMHI?
Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use ZIMHI.
What are the possible side effects of ZIMHI?
ZIMHI may cause serious side effects, including:
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.
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 store ZIMHI?
Keep ZIMHI and all medicines out of the reach of children.
General information about the safe and effective use of ZIMHI.
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 in ZIMHI?
Active ingredient: naloxone hydrochloride
Inactive ingredients: sodium chloride, hydrochloric acid to adjust pH, and water for injection.
ZIMHI is not made with natural rubber latex.
ZIMHI is a registered trademark of Adamis Pharmaceuticals Corporation.
INSTRUCTIONS FOR USE
ZIMHI™
(ZIM-hye)
(naloxone hydrochloride injection)
Prefilled syringe
Use ZIMHI for known or suspected opioid overdose in adults and children.
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.
Read this Instructions for Use carefully before you use this product.
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
ZIMHI works like a standard prefilled syringe.
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ZIMHI is injected downwards, into the middle of the outer thigh, (as shown), through clothing if needed.
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Ready to Use ZIMHI
1. Place the patient on their back.
When ready to inject, pull off cap to expose needle.
2. Do not put finger on top of the device.
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.
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3. After needle is in thigh: Push the plunger all the way down until it clicks and hold for 2 seconds.
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4. After Use
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.
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5. Get Help
Get emergency medical help now
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Tell healthcare provider that you gave an injection of naloxone hydrochloride.
Turn the patient on their side (recovery position) after giving ZIMHI.
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Use second syringe if needed
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You may need a second ZIMHI syringe if symptoms continue or return.
If symptoms return after an injection with ZIMHI, an additional injection using another ZIMHI prefilled syringe may be needed. Give additional injections using a new ZIMHI prefilled 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
For more information see Patient Information sheet or ask your healthcare provider.
How to Store - Keep ZIMHI in its plastic case nearby and ready for use at all times.
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 the ZIMHI with a new one.
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 the ZIMHIM in its case to a healthcare provider or hospital emergency room.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
