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`Adapt & Opiant Exhibit 2018
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 1
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`Volume 52 Number 6 of naloxone (0.4 mg.). The ventricular fibrillation was unresponsive to defibrillation, epinephrine, and closed-chest cardiac massage. The second patient received diazepam, meperidine, thiopental, succi- nylcholine, topical lidocaine, halothane, enflurane, nitrous oxide, and curare and experienced respirato- ry and cardiac arrest after intravenous administra- tion of naioxone (0.2 mg.). Normal sinus rhythm and respiratory rate were eventually restored, but the patient never recovered consciousness and died on the eighth postoperative day. DISCUSSION These reports are most disconcerting to all who have previously considered naloxone to be an in- nocuous drug except to the opioid addict. Yet a most basic principle of pharmacology dictates that no drug has a single action. It would now appear that naloxone has serious adverse cardiovascular effects in certain patients. Most of the authors of these case reports attribute the adverse cardiovascular effects of naloxone to a massive endogenous release of catecholamines (epi- nephrine and norepinephrine) from the adrenal medulla in response to the exacerbation of acute postoperative pain resulting from the abrupt rever- sal of narcotic analgesia. However, it has been reported6-” that naloxone increases pulse rate and left ventricular cardiac work in healthy patients. It is possible that naloxone may displace morphine from central nervous system opioid receptor sites, result- ing in a pressor effect from the free narcotic ago- nist.g Other possible explanations for the adverse cardiovascular effects of naloxone may include a previously unknown effect of the drug on peripheral opioid receptors outside the central nervous system or a drug-drug interaction(s) with one or more anesthetic agents. The majority of these patients had pre-existing heart disease; the young female patients who died did not. It is possible that patients with comprom- ised left ventricular function show adverse effects of pulmonary edema and ventricular fibrillation, while patients with good coronary function respond with atria1 fibrillation.’ It may also be true that these pressor effects of naloxone go undetected in healthy patients, since close cardiovascular monitoring is not routine in such patients. SUMMARY AND CONCLUSIONS It is now apparent that naloxone (Narcan) can no longer be considered an innocuous drug. Several reports have appeared associating adverse cardio- Naloxone-associated morbidity and mortality 603 vascular effects with the use of naloxone as an opioid antagonist. Severe hypertension, cardiac arrhythmias, pulmonary edema, and fatal cardiac arrest have occurred in both healthy and medically compromised patients. These adverse effects may be more severe when naloxone unmasks pain sup- pressed by morphine and other opioid analgesics and may be dose related. When naloxone is used to treat narcotic overdos- age, it would appear prudent to employ as low a dose as possible, monitor the blood pressure for at least 10 minutes after naloxone administration, and have ready access to antihypertensive medication.’ Nitroprusside would appear to be the safest and most effective agent for the management of hyper- tensive crisis.‘O This would hold particularly true in patients with pre-existing heart disease and those whose pain is masked by narcotic analgesics. If hypertension should occur, immediate transporta- tion of the patient to a medical facility would appear most advisable. REFERENCES Tanaka, G. Y.: Hypertensive Reaction to Naloxone, J.A.M.A. 228: 25-26, 1974. Michaelis. L. L., Hickey, P. R., Clark. T. A., and Dixon, W. M.: Ventricular irritability Associated With the Use of Naloxone Hydrochloride, Ann. Thorac. Surg. 18: 608-614, 1974. Flacke, J. W., Flacke, W. E., and Williams, G. D.: Acute Pulmonary Edema Following Naloxone Reversal of High- Dose Morphine Anesthesia. Anesthesioloev. 47: 376-378, 1977. . Vd Azar, I., and Tumdorf, H.: Severe Hypertension and Multi- ple Atria1 Premature Contractions Following Naloxone Administration, Anesth. Analg. 58: 524-525, 1979. 5. Andree. R. A.: Sudden Death Following Naloxone Adminis- tration. Anesth. Analg. 59: 782-784, 1980. 6. Desmonts. J. M.. Bohm, G., and Cruderc. E.: Hemodynamic Responses to Low Doses of Naloxone After Narcotic-Nitrous Oxide Anesthesia, Anesthesiology 49: 12-16, 1978. 7. Tigerstedt, I.. and Tannisto. T.: Effect of Naloxone Reversal on Carbon Dioxide Output, Oxygen Uptake and Cardiac Index During Recovery From Fentanyl-Supplemented Anes- thesia, Acta Anesthesiol. Stand. 22: 158-166, 1978. 8. Huse. K., Hartung, E.. and Nadjmabadi. M. H.: The Effects of Naloxone (Narcan) on Circulation and Respiration After Neurolept Anesthesia for Neurosurgical Operations, Anes- thesist 23: 493-499, 1974. 9. Freye. E.: Cardiovascular Effects of High Dosage of Fenta- nyl. Meperidine and Naloxone in Dogs. Anesth. Analg. 53: 40-47. 1974. 10. Cohn, J. N., and Burke, L. P.: Nitroprusside. Ann. Intern. Med. 91: 752. 1979. Reprint requests to: Dr. Thomas J. Pallasch University of Southern California School of Dentistry P.O. Box 77951 Los Angeles, Calif. 90007
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`Adapt & Opiant Exhibit 2018
`Nalox-1 Pharmaceuticals, LLC v. Adapt Pharma Limited et al.
`IPR2019-00697
`Page 2
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