FDA Label for Zimhi

View Indications, Usage & Precautions

Zimhi Product Label

The following document was submitted to the FDA by the labeler of this product Zmi Pharma Inc.. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.

1. Indications And Usage

ZIMHI is indicated in adults and pediatric patients for:

the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

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.

2.1Important Administration Instructions

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.

Do not attempt to reuse ZIMHI. Each ZIMHI contains a single-dose of naloxone hydrochloride for single-dose injection. - zimhi 01

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:

Seek emergency medical care immediately after use. Because the duration of action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer repeated doses of ZIMHI as necessary. Always seek emergency medical assistance in the event of a suspected potentially life-threatening opioid emergency after administration of the first dose of ZIMHI.
Additional doses of ZIMHI may be required until emergency medical assistance becomes available [ see Dosage and Administration (2.2)].
Administer ZIMHI according to the Instructions for Use and the printed instructions on the device label:
- Place the patient in the supine position.
- Inject ZIMHI intramuscularly or subcutaneously into the anterolateral aspect of the thigh with the needle facing downwards. Inject through clothing if necessary [ seeInstructions for Use].
- Embed the needle completely before transferring the thumb to the syringe plunger.

- 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.

2.2Dosing Information

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.

3.Dosage Forms And Strengths

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).

4.Contraindications

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

5.1Risk Of Recurrent Respiratory And Central Nervous System Depression

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.

5.2Risk Of Limited Efficacy With Partial Agonists Or Mixed Agonist/Antagonists

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [ see Dosage and Administration (2)]. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

5.3Precipitation Of Severe Opioid Withdrawal

The use of 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)].

5.4Risk Ofaccidentalneedlestickinjury

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.

6.Adverse Reactions

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

Precipitation of Severe Opioid Withdrawal [ see Warnings and Precautions (5.3)]

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 (5.3)].

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)].

8.1Pregnancy

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.

8.2Lactation

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.

8.4Pediatric Use

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)].

8.5Geriatric Use

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.

11.Description

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:

Structural formula for naloxone hydrochloride - zimhi 04

C ₁₉H ₂₁NO ₄• HCl

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.

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.

12.1Mechanism Of Action

Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.

Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2Pharmacodynamics

When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration.

The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

12.3Pharmacokinetics

In a pharmacokinetic study 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

Parameter	Intramuscular Injection of 5 mg ZIMHI (N = 14)	Intramuscular Injection of 2 mg Naloxone HCl (N = 14)
T _max(h)*	0.25 (0.17, 0.52)	0.25 (0.05, 3.00)
C _max(ng/mL)	17.2 (44)	3.58 (58.1)
AUC _0-t(ng.h/mL)	26.2 (21.5)	9.43 (23.8)
AUC _0-inf(ng.h/mL)	26.6 (21.2)	9.97 (22.6)
AUC _0-0.04h(ng.h/mL)	0.02 (208)	0.01 (164)
AUC _0-0.08h(ng.h/mL)	0.15 (117)	0.04 (128)
T _1/2(h)	1.50 (15.2)	1.86 (28.9)

*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

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 Naloxo - zimhi 05

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.

13.1Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed.

Mutagenesis

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

Impairment of Fertility

Reproduction studies conducted in mice and rats at doses 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.

16.1How Supplied

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

16.2Storage And Handling

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.

17.Patient Counseling Information

Advise the patient and family members or caregivers to read the FDA-approved patient labeling ( Patient Informationand 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:

ZIMHI is for the emergency treatment of known or suspected overdose.
It is administered by a caregiver according to the Instructions for Use.
After administration, the caregiver should get emergency help immediately.

Recognition of Opioid Overdose

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:

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

Principal Display Panel

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

NDC 84571-140-02Rx OnlyZIMHITM(naloxone HCL Injection, USP)5 mg/ 0.5 mL - zimhi 14

* Please review the disclaimer below.

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