------------------------WARNINGS AND PRECAUTIONS----------------------­
`
`• Due to the duration of action, keep the patient under continued surveillance and
`
`
`
`
`
`repeated doses of naloxone should be administered, as necessary, while awaiting
`
`
`
`emergency medical assistance. (5.1)
`
`
`• Other supportive and/or resuscitative measures may be helpful while awaiting
`
`
`
`
`emergency medical assistance. (5.1)
`
`
`• Reversal of respiratory depression by partial agonists or mixed
`
`
`agonists/antagonists such as buprenorphine and pentazocine, may be incomplete.
`
`
`
`
`
`
`(5.2)
`
`• Use in patients who are opioid dependent may precipitate acute abstinence
`
`
`
`syndrome. (5.3)
`
`
`• Patients with pre-existing cardiac disease or patients who have received
`
`
`
`medications with potential adverse cardiovascular effects should be monitored in
`
`
`an appropriate healthcare setting (5.3)
`
`• In neonates, opioid withdrawal may be life-threatening if not recognized and
`
`
`properly treated. (5 3)
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`The following adverse reactions have been identified during use of naloxone
`
`
`
`
`hydrochloride in the post-operative setting: 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. (6)
`
`
`
`
`Abrupt reversal of opioid effects in persons who were physically dependent on
`
`
`
`opioids has precipitated signs and symptoms of opioid withdrawal including: body
`
`
`
`
`aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness,
`
`shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or
`
`
`
`vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate,
`
`
`
`
`
`opioid withdrawal signs and symptoms also included: convulsions, excessive crying,
`
`
`
`hyperactive reflexes. (6)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact kaleo, Inc. at
`
`
`
`1-855-773-8946 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`
`
`approved patient labeling
`
`
`
`
`
`
`
`
`
`
`
`Revised: 4/2014
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use EVZIO
` safely and effectively. See full prescribing information for EVZIO.
`
`
`
`
`
`
`
`
` EVZIO (naloxone hydrochloride injection) Auto-Injector for
` intramuscular or subcutaneous use
`
`
` Initial U.S. Approval: 1971
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
` EVZIO 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. (1)
`
`
` EVZIO is intended for immediate administration as emergency therapy in
`
`
`
` settings where opioids may be present. (1)
`
` EVZIO is not a substitute for emergency medical care. (1)
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`• EVZIO is for intramuscular or subcutaneous use only. (2.1)
`
`
`
`
`
`• Seek emergency medical care immediately after use. (2.1)
`
`
`
`• Administer EVZIO to adult or pediatric patients into the anterolateral
`
`
`
`
`
`aspect of the thigh, through clothing if necessary. (2.2)
`
`• Additional doses may be administered every 2 to 3 minutes until
`
`
`
`
`
`emergency medical assistance arrives. (2.2)
`
`
`• In pediatric patients under the age of one, the caregiver should pinch the
`
`
`
`
`
`
`thigh muscle while administering the dose. (2.2)
`
`
`• If the electronic voice instruction system does not operate properly,
`
`
`
`
`
`EVZIO will still deliver the intended dose of naloxone hydrochloride
`
`
`when used according to the printed instructions on the flat surface of
`
`
`
`its label. (2.1)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`Injection: 0.4 mg/0.4 mL naloxone hydrochloride solution in a pre-filled
`
`
`
`
`
`
`auto-injector. (3)
`
`
`
`------------------------------CONTRAINDICATIONS------------------------------­
`Patients known to be hypersensitive to naloxone hydrochloride (4)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 1
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`11 DESCRIPTION
`
`
`
`1
`
`
`2
`
`
`3
`
`
`4
`
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`
`
`Important Administration Instructions
`
`
`2.2 Dosing Information
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Duration of Effect
`
`
`
`
`5.2 Limited Efficacy with Partial Agonists or Mixed
`
`
`
`
`Agonist/Antagonists
`
`
`5.3 Precipitation of Severe Opioid Withdrawal
`
`
`
`6
`
`
`8
`
`
`ADVERSE REACTIONS
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric use
`
`
`
`8.5 Geriatric Use
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`
`16.2 Storage and Handling
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`INDICATIONS AND USAGE
`
`1
`
` EVZIO 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.
`
`
`
`EVZIO is intended for immediate administration as emergency therapy in settings where opioids
`
`may be present.
`
`
`
`
`EVZIO is not a substitute for emergency medical care.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`2.1
` Important Administration Instructions
`
`
`
` • EVZIO is for intramuscular and subcutaneous use only.
`
`
` • Because treatment of 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
`
`
` EVZIO and the Instructions for Use.
`
`
`
` • Seek emergency medical care immediately after use. Since 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, and administer repeated doses of EVZIO 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 EVZIO.
` • Additional doses of EVZIO may be required until emergency medical assistance becomes
`
`
`
`
` available.
`
`
`
`
`
` • Do not attempt to reuse EVZIO. Each EVZIO contains a single dose of naloxone.
`
`
` • Visually inspect EVZIO through the viewing window for particulate matter and discoloration
`
`
`
`
` prior to administration. Do not administer unless the solution is clear and the glass container is
`
`
`
`
` undamaged.
`
`
`The Instructions for Use should be read by the patient or caregiver at the time they receive a
`
`
`
`
`
`prescription for EVZIO. Provide the following instructions to the patient or caregiver:
`
`
`
`
`• EVZIO must be administered according to the printed instructions on the device label or the
`
`
`
`
`
`
`electronic voice instructions (EVZIO contains a speaker that provides voice instructions to guide
`
`
`
`the user through each step of the injection). If the EVZIO electronic voice instruction system
`
`
`
`
`does not operate properly, EVZIO will still deliver the intended dose of naloxone
`
`
`
`
`
`hydrochloride when used according to the printed instructions on its label.
`
`
`
`• Once the red safety guard is removed, EVZIO must be used immediately or disposed of properly.
`
`
`
`
`
`
`Do not attempt to replace the red safety guard once it is removed.
`
`
`
`
`
`Upon actuation, EVZIO automatically inserts the needle intramuscularly or subcutaneously, delivers
`
`
`0.4 mg naloxone hydrochloride injection, and retracts the needle fully into its housing. Post injection,
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 3
`
`

`

`
`
` the black base locks in place, a red indicator appears in the viewing window, and electronic visual and
`
`
`
` audible instructions signal that EVZIO has delivered the intended dose of naloxone hydrochloride and
` instructs the user to seek emergency medical attention.
`
`
`
`
`2.2 Dosing Information
`
`
`
`
`
`
`Administer the initial dose of EVZIO 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 EVZIO 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 EVZIO
`
`
`
`
`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, another EVZIO dose may be administered.
`
`
`
`
`If there is still no response and additional doses are available, additional EVZIO doses 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.
`
`
`Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as
`
`
`buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone.
`
`
`
`
`Dosing in Adults and Pediatric Patients over Age One
`Instruct patients or their caregivers to administer EVZIO according to the Instructions for Use,
`
`
`intramuscularly or subcutaneously.
`
`Dosing in Pediatric Patients under Age One
`
`
`In pediatric patients under the age of one, the caregiver should pinch the thigh muscle while
`
`
`
`
`administering EVZIO.
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` Injection: 0.4 mg/0.4 mL naloxone hydrochloride solution in a pre-filled auto-injector. Each
`
`
` EVZIO delivers 0.4 mg naloxone hydrochloride injection (0.4 mL).
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
` EVZIO is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any
`
` of the other ingredients.
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`5.1 Duration of Effect
`
`
`The duration of action of most opioids is likely to exceed that of EVZIO resulting in a return of
`respiratory and/or central nervous system depression after an initial improvement in symptoms.
`
`Therefore, it is necessary to seek immediate emergency medical assistance after delivering the first
`
`
`
`
`
`
`
`dose of EVZIO, keep the patient under continued surveillance, and repeat doses of EVZIO as
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 4
`
`

`

`
`
`
`
`necessary. Additional supportive and/or resuscitative measures may be helpful while awaiting
`
`emergency medical assistance.
`
`
`
`
`
`
`
`
`5.2 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. Large doses of naloxone hydrochloride are
`
`
`
`
`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. 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 EVZIO 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.
`
`
`
`
`
`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 occurred in
`
`patients most of whom had pre-existing cardiovascular disorders or received other drugs which may
`
`
`
`
`have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not
`
`
`
`
`
`been established, after use of naloxone hydrochloride, patients with pre-existing cardiac disease or
`
`
`patients who have received medications with potential adverse cardiovascular effects should be
`
`
`
`monitored 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.
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
` The following serious adverse reactions are discussed elsewhere in the labeling:
`
`
`
`
` • Duration of effect [see Warnings and Precautions (5.1]]
`
`
`
` • Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`
` 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
`
`
`Reference ID: 3482803
`
`
`
`
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 5
`
`

`

`
`
` 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)].
`
`
`
`
`Abrupt reversal of opioid effects in persons who were physically dependent on opioids has
`
`
`
`precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches,
`
`fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling,
`nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps,
`
`increased blood pressure, tachycardia. In the neonate, opioid withdrawal signs and symptoms
`
`
`
`also included: convulsions, excessive crying, hyperactive reflexes [see Warnings and
`
`
`
`Precautions (5.3)].
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
` Pregnancy Category B
`
`
` Risk Summary
`
`
`
` There are no adequate and well-controlled studies with EVZIO in pregnant women. Animal
`
`
`
`
`
` studies were conducted with naloxone hydrochloride given during organogenesis in mice and rats
`
` at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day. These studies
` demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Because animal
`
`
`
`
`
`
` reproduction studies are not always predictive of human response, EVZIO should be used during
` pregnancy only if clearly needed.
`
`
`
`
`
`
`
`
` Clinical Considerations
`
`
`
` Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus as well
`
` as in the opioid-dependent mother. The fetus should be evaluated for signs of distress after
`
`
` EVZIO is used. Careful monitoring is needed until the fetus and mother are stabilized.
`
`
`
`
` 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/m2). These studies demonstrated no embryotoxic or teratogenic effects
`
`
`due to naloxone hydrochloride.
`
`
` 8.3 Nursing Mothers
`
`
` It is not known whether naloxone hydrochloride is present in human milk. Because many drugs are
`
`
`
`
`
`
`
`
`
` present in human milk, exercise caution when EVZIO is administered to a nursing woman.
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 6
`
`

`

`
`
`
` 8.4 Pediatric Use
` The safety and effectiveness of EVZIO (for intramuscular and subcutaneous use) have been
`
`
`
`
`
`
` established in pediatric patients for known or suspected opioid overdose, as manifested by
` respiratory and/or central nervous system depression. Use of naloxone hydrochloride in
`
`
`
`
`
`
`
` pediatric patients is supported by evidence from adequate and well-controlled studies of
`
` naloxone hydrochloride in adults with additional data from 15 clinical studies (controlled and
`
`
` uncontrolled) in which neonates and pediatric patients received parenteral naloxone in doses
`
`
` ranging from 0.005 mg/kg to 0.01 mg/kg. Safety and effectiveness are also supported by use of
`
`
`
`
`
` other naloxone hydrochloride products in the post-marketing setting as well as data available in
`
`
`
`
` the medical literature and clinical practice guidelines.
`
`
`
`
`
`
`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 dramatically 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 may result in an
`
`
`abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal
`
`syndrome. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults,
`
`may be life-threatening and should be treated according to protocols developed by neonatology
`
`
`experts [see Warnings and Precautions (5.3)].
`
`
`
`
`
`
`
`In neonates and pediatric patients less than 1 year of age, careful observation of the
`
`
`
`administration site for evidence of residual needle parts and/or signs of infection is warranted
`[see Dosage and Administration (2.1)].
`
`
`
` 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.
`
`11 DESCRIPTION
`
`
` EVZIO (naloxone hydrochloride injection, USP) is a pre-filled, single-use auto-injector. EVZIO 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:
`
`
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 7
`
`

`

`
`
`
`
`
`
` C19H21NO4• HCl
`
`
`
` M.W. 363.84
`
`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 0.4 mL in EVZIO contains inactive ingredients of 3.34 mg of sodium chloride, hydrochloric acid
`
`
`
`
`
`
`to adjust pH, and water for injection. The pH range is 3.0 to 4.5.
`
`
`
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 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 one pharmacokinetic study in 30 healthy subjects, a single 0.4 mg subcutaneous or intramuscular
`
`
`
` naloxone injection administered using EVZIO provides equivalent naloxone AUC and 15% greater
`
`
`
` naloxone Cmax in comparison to a single 0.4 mg subcutaneous or intramuscular naloxone injection
`
`
`
`
`
`
` administered using a standard syringe.
`
`
`
`
`
`
`
`
`
`
`
` Following a single EVZIO injection, the median Tmax of naloxone was reached at 15 minutes (range
`
`
`
`
` 5 minutes to 1.2 hours), with a mean (± SD) Cmax value of 1.24 (± 0.64) ng/mL. The mean (± SD)
`
`
`
`
`
`
`
`
` plasma half-life of naloxone in healthy adults was 1.28 (± 0.48) hours. In the same study, following
`
`
`
`
`
`
`
`
`
`
` administration of a single dose of 0.4 mg naloxone injection using a standard syringe, the median
`
`
` Tmax was 20 minutes (range 5 minutes to 2.03 hours) and the mean (± SD) Cmax value was 1.07 (±
`
`
`
`
` 0.48) ng/mL. The mean (± SD) plasma half-life was 1.36 (± 0.32) hours.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 8
`
`

`

`
`
` 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.
`
`
`
` Metabolism
`Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with
`
`
`
`naloxone-3-glucoronide as the major metabolite.
`
`
`Elimination
`
`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. Following a single EVZIO injection, the
`
`
`
`mean (± SD) plasma half-life of naloxone in healthy adults was 1.28 (± 0.48) hours. In a neonatal
`
`
`
`
`
`study of naloxone injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.
`
`
`
`
`
`
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, 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 a 50 kg human given 10 mg/day (when based on surface area or mg/m2), demonstrated no adverse
`
`
`effect of naloxone hydrochloride on fertility.
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Store at controlled room temperature 15°C to 25°C (59°F to 77°F) excursions permitted between 4°C
`
`
`
`
`
`
`
`
`Reference ID: 3482803
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` 16.1 How Supplied
`
`
`
` Carton containing two EVZIO (naloxone hydrochloride injection, USP) 0.4 mg auto-injectors
`
`
` and a single Trainer for EVZIO - NDC 60842-030-01
`
`
`
`
` 16.2 Storage and Handling
`
`
` Store EVZIO in the outer case provided.
`
`
` and 40°C (between 39°F and 104°F).
`
`
`
`
`
`
`
`
`
`
`
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 9
`
`

`

`
`
` Before using, check to make sure the solution in the auto-injector is not discolored. Replace EVZIO if
`
`
` the solution is discolored or contains a precipitate.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
` Advise the patient and family members or caregivers to read the FDA-approved patient labeling
`
`
`
` (Instructions for Use).
`
`
`Instruct patients and their family members or caregivers to:
`
`
`
`
`
`• Become familiar with the following information contained in the carton as soon as they
`
`
`receive EVZIO:
`o EVZIO Instructions for Use
`
`
`
`
`o Trainer for EVZIO Instructions for Use
`
`
`
`o Trainer for EVZIO
`
`
`
`
`
`
`● Practice using the Trainer before EVZIO is needed.
`o Each EVZIO (which is purple and yellow) can only be used one time; however,
`
`
`
`
`
`
`
`
`
`the Trainer (which is black and white) can be re-used for training purposes and its
`
`
`
`red safety guard can be removed and replaced.
`o Both EVZIO and the Trainer for EVZIO incorporate the electronic voice
`
`
`
`
`instruction system.
`
`
`
`
`● Make sure EVZIO is present whenever persons may be intentionally or accidentally
`
`
`exposed to an opioid to treat serious opioid overdose (i.e., opioid emergencies).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Instruct the patients and their family members or caregivers how to recognize the signs and
`
`
`
`symptoms of an opioid overdose requiring the use of EVZIO such as the following:
`
`
`
`
`
`
`
`
`
` • Extreme sleepiness - inability to awaken a patient verbally or upon a firm sternal rub.
`
`
` • Breathing problems - this can range from slow or shallow breathing to no breathing in a
`
`
`
`
` patient who cannot be awakened.
`
`
` • Other signs and symptoms that may accompany sleepiness and breathing problems
`
`
` include the following:
`
`
` o Extremely small pupils (the black circle in the center of the colored part of the eye)
`
`
` sometimes called “pinpoint pupils.”
` o Slow heartbeat and/or low blood pressure.
`
`
`
`Instruct them that when in doubt, if a patient is unresponsive, and an opioid overdose is
`
`suspected, administer EVZIO as quickly as possible because prolonged respiratory depression
`
`may result in damage to the central nervous system or death. Instruct them to seek emergency
`
`
`
`medical assistance after administering the first dose of EVZIO.
`
`
`
`Duration of Effect
`
`
`
`
`
`Instruct patients and their family members or caregivers that since the duration of action of
`
`
`
`most opioids may exceed that of naloxone, seek immediate emergency medical assistance,
`
`keep the patient under continued surveillance, and administer repeated doses of EVZIO as
`
`necessary.
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 10
`
`

`

`
`
`
`•
`
` Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists
`
`
`Instruct patients and their family members or caregivers that the reversal of respiratory
`
`
`
`depression by partial agonists or mixed agonist/antagonists such as buprenorphine and
`
`pentazocine, may be incomplete.
`
`
` Precipitation of Severe Opioid Withdrawal
`
`
`Instruct patients and their family members or caregivers that the use of EVZIO 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.
`
`
`
`Administration Instructions
`
`Instruct patients and their family members or caregivers about the following important
`
`
`
`information:
`
`
`• EVZIO is user actuated and may be administered through clothing [e.g., pants, jeans,
`
`
`etc.] if necessary.
`
`Inject EVZIO while pressing into the anterolateral aspect of the thigh. In pediatric
`
`
`
`
`patients less than 1 year of age, pinch the thigh muscle while administering EVZIO.
`
`
`
`• Upon actuation, EVZIO automatically inserts the needle intramuscularly or subcutaneously,
`
`
`
`delivers the naloxone, and retracts the needle fully into its housing. The needle is not visible
`
`
`
`
`
`before, during, or after injection.
`
`• Each EVZIO can only be used one time.
`
`
`If the electronic voice instruction system on EVZIO does not work properly, EVZIO will still
`
`
`•
`deliver the intended dose of naloxone hydrochloride when used according to the printed
`
`instructions on its label.
`
`• The electronic voice instructions are independent of activating EVZIO and are not required
`
`
`
`to wait for the voice instructions to be completed prior to moving to the next step in the
`
`injection process.
`
`• Post-injection, the black base locks in place, a red indicator appears in the viewing window
`
`
`
`and electronic visual and audible instructions signal that EVZIO has delivered the intended
`dose of naloxone hydrochloride.
`
`• EVZIO’s red safety guard should not be replaced under any circumstances. However, the
`
`
`
`
`Trainer is designed for re-use and its red safety guard can be removed and replaced.
`
`
`It is recommended that patients and caregivers become familiar with the training device
`
`provided and read the Instructions for Use; however, untrained caregivers or family members
`
`
`
`
`should still attempt to use EVZIO during a suspected opioid overdose while awaiting
`
`
`
`definitive emergency medical care.
`
`• Periodically visually inspect the naloxone solution through the viewing window. If the
`
`
`
`
`solution is discolored, cloudy, or contains solid particles, replace it with a new EVZIO.
`
`
`• Replace EVZIO before its expiration date.
`
`
`
`---------------------------------------------------------------------------------------------------------------
`
`
`•
`
`
`
`Reference ID: 3482803
`
`Adapt & Opiant Exhibit 2008
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00699
`Page 11
`
`

`

`
`
`
`
`Manufactured for:
`
`
`kaleo, Inc.
`
`
`
`Richmond, VA 23219
`
`
`
`*For California Only: This product uses batteries containing Perchlorate Material – special
`
`
`
`
`
`handling may apply. See www.dtsc.ca.gov/hazardouswaste/perchlorate
`
`
`
`
`
`Reference ID: