1 INDICATIONS AND USAGE ZURNAI is indicated for the emergency treatment of known or suspected opioid overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression.

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

ZURNAI is not a substitute for emergency medical care.

ZURNAI is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression.

( 1 ) ZURNAI is intended for immediate administration as emergency therapy in settings where opioids may be present.

( 1 ) ZURNAI is not a substitute for emergency medical care.

( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Recurrent Respiratory and Central Nervous System Depression [see Warnings and Precautions (5.1) ] Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence > 5%) are feeling hot, nausea, headache, dizziness, chills, vomiting, allodynia, palpitations, tinnitus, ear discomfort, feeling abnormal, burning sensation, hot flush, and irritability.

( 6 ) To report Suspected Adverse Reactions, contact Knoa Pharma LLC at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Adult Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ZURNAI is supported by pharmacokinetic and pharmacodynamic studies of ZURNAI in healthy subjects in a normal state and under steady state opioid agonism.

The following adverse reactions were observed.

In a pharmacokinetic study (NAL1005) of 21 healthy adult volunteers exposed to one dose of ZURNAI the most common adverse reactions were: dizziness and headache.

In a pharmacodynamic study (NAL1004) of 23 healthy adult volunteers exposed to one dose of ZURNAI, the most common adverse reactions were: feeling hot, chills, nausea, allodynia, and headache.

Table 1: Relative Frequencies of Most Common Adverse Reactions that Occurred in Greater than 5% of Subjects in Study NAL1004 and Study NAL1005 (pooled dataset) Nalmefene Auto-Injector 1.5 mg IM System Organ Class Preferred Term Pooled NAL1004 and NAL1005 N=44 n (%) Study NAL1004 N=23 n (%) Study NAL1005 N=21 n (%) Any AR 28 (63.6) 21 (91.3) 7 (33.3) Cardiac disorders Palpitations 4 (9.1) 4 (17.4) 0 Ear and labyrinth disorders Tinnitus 4 (9.1) 4 (17.4) 0 Ear discomfort 3 (6.8) 3 (13.0) 0 Gastrointestinal disorders Nausea 8 (18.2) 6 (26.1) 2 (9.5) Vomiting 5 (11.4) 3 (13.0) 2 (9.5) General disorders and administration site conditions Feeling hot 11 (25.0) 11 (47.8) 0 Chills 6 (13.6) 6 (26.1) 0 Feeling abnormal 3 (6.8) 3 (13.0) 0 Nervous system disorders Dizziness 7 (15.9) 4 (17.4) 3 (14.3) Headache 8 (18.2) 5 (21.7) 3 (14.3) Allodynia 5 (11.4) 5 (21.7) 0 Burning sensation 3 (6.8) 3 (13.0) 0 Psychiatric disorders Irritability 3 (6.8) 3 (13.0) 0 Vascular disorders Hot flush 3 (6.8) 3 (13.0) 0 Adverse reaction information was obtained following administration of nalmefene hydrochloride injection to 152 healthy volunteers and to 1127 patients in controlled clinical trials for the treatment of opioid overdose or for postoperative opioid reversal.

TABLE 2: Relative Frequencies of Common Adverse Reactions with an Incidence Greater than 1% (all patients, all clinical settings) Adverse Reaction Nalmefene N=1127 Placebo N=77 Nausea 18% 6% Vomiting 9% 4% Tachycardia 5% - Hypertension 5% - Postoperative pain 4% N/A Fever 3% - Dizziness 3% 1% Headache 1% 4% Chills 1% - Hypotension 1% - Vasodilatation 1% - Incidence less than 1% CARDIOVASCULAR: Bradycardia, arrhythmia DIGESTIVE: Diarrhea, dry mouth NERVOUS SYSTEM: Somnolence, depression, agitation, nervousness, tremor, confusion, withdrawal syndrome, myoclonus RESPIRATORY: Pharyngitis SKIN: Pruritus UROGENITAL: Urinary retention The incidence of adverse events was highest in patients who received more than the recommended dose of nalmefene hydrochloride injection.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of nalmefene.

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.

Abrupt reversal of opioid depression using nalmefene in both postoperative and emergency department settings has resulted in nausea, vomiting, sweating, tremulousness, seizures, and cardiovascular instability including tachycardia, hypotension, hypertension, 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.

In persons who were physically dependent on opioids, abrupt reversal of opioid effects has precipitated an acute withdrawal syndrome.

Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shiver or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia.

In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose.

In the neonate, opioid withdrawal symptoms also included convulsions, excessive crying, and hyperactive reflexes.