Zimhi Drug Information

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.

ZIMHI is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. 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.

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. 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.

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. - 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. - Do NOT attempt to re-cap the needle with the needle cap once it has been removed . - 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.

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

Dosing 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.

6. ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Precipitation of Severe Opioid Withdrawal 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.

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. The following adverse reactions were most commonly observed in ZIMHI clinical studies: dizziness and injection site erythema. To report SUSPECTED ADVERSE REACTIONS, contact ZMI Pharma Corporation at 1-800-230-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pregnancy Risk Summary 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. 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.

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.. 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..

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