2.1 Important 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.

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 [see Instructions 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.

2.2 Dosing Information

5.1 Risk 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.

5.2 Risk 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.

5.3 Precipitation 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)].

5.4 Risk of Accidental Needlestick Injury

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric 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)].

8.5 Geriatric 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.

12.1 Mechanism 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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 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.

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

a)

b)

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

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

NDC78670-140-11: Case containing one 5 mg/0.5 mL single-dose, pre-filled syringe

NDC78670-140-02: Carton containing two cases, each of which contain one 5 mg/0.5 mL single-dose, pre-filled syringe

16.2 Storage and Handling

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.

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.

Risk of Recurrent Respiratory and Central Nervous System Depression

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)].

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

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of ZIMHI [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].

Precipitation of Severe Opioid Withdrawal

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)].

Administration Instructions

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

• 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.
• Each syringe is for a single-dose injection.
• 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).
• 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 [see Dosage and Administration (2.1)].
• Place the patient in the supine position.
• Inject ZIMHI into the anterolateral aspect of the thigh (through clothing, if necessary). Instruct patients to the correct location for injection.
• 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.
• Seek emergency medical care immediately following administration of ZIMHI.
• Place the patient in the lateral recumbent position (recovery position) as shown in the Instructions for Use.
• Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.
• 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.
• 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 Adamis Pharmacovigilance at (800) 230-3935.
• 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.
• 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.
• Replace ZIMHI before its expiration date.