`
`Gregory W. Terman M.D., Ph.D.
`Professor
`Department of Anesthesiology and Pain Medicine
`and the Graduate Program in Neurobiology
`Mayday Pain and Society Fellow
`University of Washington
`Seattle, Washington
`
`98195
`
`gwt@u.washington.edu
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 1
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`Naloxone: Effects and Side Effects
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`Specificity
`Toxicology
`Unmasking Disease
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 2
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 3
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 4
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`Naloxone: Effects and Side Effects
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`Am. J. Med. Sci. 245: 23-30, 1963
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 5
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 6
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 7
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 8
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 9
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`Naloxone: Effects and Side Effects
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`Specificity
`Toxicology
`Unmasking Disease
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 10
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`Naloxone: Effects and Side Effects
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`Toxicology in Rats:
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 11
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`Naloxone: Effects and Side Effects
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`Toxicology in People:
`Packaged 0.4 mg/ml and recommended at 0.4-0.8 mg IV.
`We treat opiate overdose in hospital with 0.04 mg IV
`with repeated doses q2 min as necessary.
`In opiate naïve patients without pain IV doses up to 5.4
`mg/kg boluses and 4 mg/kg/h have been administered
`without adverse effects (Clarke et al., Emerg Med J 22:
`616-616, 2005) (although mild elevations in blood
`pressure and decreased performance on memory tests
`have been reported with doses over 20 mg)
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 12
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 13
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`Naloxone: Effects and Side Effects
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`Specificity
`Toxicology
`Unmasking Disease
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 14
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 15
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 16
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`
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`Naloxone: Effects and Side Effects
`Opiate Withdrawal:
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`Terman et al, British Journal of Pharmacology, 2004
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 17
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 18
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 19
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`Naloxone: Effects and Side Effects
`Cardiovascular effects
`Withdrawal induced catecholamine release (e.g., sweating)
`Tachycardia or other arrhythmia (myocardial
`ischemia) morbidity
`In patients with other drugs on board (e.g.,
`cocaine)
`In patients with pre-existing cardiac disease
`In patients with hypoxia and/or hypercarbia
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 20
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 21
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`
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`Naloxone: Effects and Side Effects
`Cardiovascular effects
`Withdrawal induced catecholamine release (e.g., sweating)
`Tachycardia or other arrhythmia (myocardial
`ischemia) morbidity
`In patients with other drugs on board (e.g.,
`cocaine)
`In patients with pre-existing cardiac disease
`In patients with hypoxia and/or hypercarbia
`Hypertension morbidity (e.g., vascular aneurysms)
`Pulmonary edema (e.g., in heart failure)
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 22
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 23
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 24
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`
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`Naloxone: Effects and Side Effects
`Cardiovascular effects
`Withdrawal induced catecholamine release (e.g., sweating)
`Tachycardia or other arrhythmia (myocardial
`ischemia) morbidity
`In patients with other drugs on board (e.g.,
`cocaine)
`In patients with pre-existing cardiac disease
`In patients with hypoxia and/or hypercarbia
`Hypertension morbidity (e.g., vascular aneurysms)
`Pulmonary edema (e.g., in heart failure) –
`perhaps most commonly post-obstructive
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 25
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`Naloxone: Effects and Side Effects
`Seizure effects
`May lower seizure thresholds for patients with prior
`seizure disorder or immediately post-ictal (i.e., after a
`seizure).
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 26
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 27
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 28
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`Naloxone: Effects and Side Effects
`Seizure effects
`Theoretically, may lower seizure thresholds for patients
`with prior seizure disorder or immediately post-ictal (i.e.,
`after a seizure).
`May unmask seizures from other drugs on board (e.g.,
`cocaine).
`May unmask seizures due to hypoxia or hypercarbia.
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 29
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 30
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 31
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 32
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`Naloxone: Effects and Side Effects
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`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 33
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`
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`Naloxone: Effects and Side Effects
` Specificity (Amazing)
` Toxicology (Forgiving)
` Unmasking Disease: Concerns
` Opiate Dependence (Withdrawal)
` Co-ingested Substances
` Hypoxemia/Hypercarbia
` Arrythmias
` Seizures
` Post-Obstructive Pulmonary Edema
` Unrecognized Re-narcotization (perhaps worse with long–
`acting prescription meds than with other opiates)
` Pain
`
`Adapt & Opiant Exhibit 2024
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00698
`Page 34
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