`
`
`
`AMN1040
`
`IPR of Patent No. 7,919,499
`
`AMN1040
`IPR of Patent No. 7,919,499
`
`

`

`1992
`PHYSCANS'
`DESK
`REFERENCE®
`
`Director of Production :
`MARJORIE A. DUFFY
`Assistant Director of Production:
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`
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`
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`
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`
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`
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`
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`
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`
`~ Copyright @1992 and published by Medical Economics Data, a division of Medical Economics Company Inc., at Montvale, N.J. 07645. All rights reserved. None of the content
`• • of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, or otherwise) without
`the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE·•·, PDR·•·, PDR For Ophthalmology •·, PDR For Nonprescription Drugs·•·, PDR Drug Interactions and
`Side Effects"' and PDR Indications Index '" are trademarl<s of Medical Economics Company Inc., registered in the United States Patent and Trademarl< Office.
`
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`
`ISBN 1-56363-003-6
`
`AMN1040
`IPR of Patent No. 7,919,499
`
`

`

`NIACINAMIDE
`B-C-Bid Capsules (Geriatric) .............. 1052
`Eldercaps (Mayrand
`Pharmaceuticals) .................................. 1359
`Eldertonic (Mayrand
`Pharmaceuticals) .................................. 1359
`Glutofac Tablets (Kenwood) ................ 1163
`.
`I.L.X. B12 Tablets Crystalline
`(Kenwood)................................................ 11 63
`May-Vita Elixir (Mayrand
`Pharmaceuticals) .................................. 1359
`Mega-B (Arco) ................................................ 607
`Natalins Rx (Mead Johnson
`Laboratories) ................................ 418, 1391
`Natalins Tablets (Mead
`Johnson Laboratories) ................ 418, 1391
`Prenate 90 Tablets (Bock) ............ : ......... 673
`Vicon Forte Capsules (Whitby) 434,2416
`NICARDIPINE HYDROCHLORIDE
`Cardene Capsules (Syntex) ........ 432, 2290
`
`318
`NAL TREXONE HYDROCHLORIDE
`Trexan Tablets (Du Pont
`Multi-Source Products) ............. : .............. 937
`NANDROLONE DECANOATE
`Deca-Durabolin (Organon) .................... 1636
`NANDROLONE PHENPROPIONATE
`Durabolin (Organon) ................................ 1.63(/
`NAPHAZOLINE HYDROCHLORIDE
`4-Way Fast Acting Nasal
`Spray (regular &
`mentholated) & Metered
`Spray Pump (regular)
`(Bristol-Myers Products) .......................... 751
`Naphcon-A Ophthalmic
`Solution (Alcon Laboratories) .............. 571
`Privine Hydrochloride 0.05%
`Nasal Solution (CillA
`Pharmaceutical) ................................... : .... 878
`Privine Hydrochloride 0.05%
`NICLOSAMIDE
`Nasal Spray (CillA
`Pharmaceutical) ........................................ 878
`.
`Niclocide Chewable Tablets
`(Miles Pharmaceutical) ············:· 420,1607
`NAPROXEN
`Naprosyn Suspension (Syntex) 432, 2297 NICOTINAMIDE
`Naprosyn Tablets (Syntex) ........ 432, 2297
`I.L.X. B12 Elixir Crystalline
`(Kenwood) ................................................ 1163
`NAPROXEN SODIUM
`NICOTINE POLACRILEX
`Anaprox and Anaprox DS
`Tablets (Syntex) .......................... 432, 2288
`Nicorette (Marion Merrell Dow) 4l7, 1335
`
`NICOTINIC ACID
`(see also under NIACIN)
`Niacor Tablets (Upsher-Smith) ............ 2376
`Nicobid (Rhone-Poulenc Rorer
`Pharmaceuticals) ........................ 427, 1846
`Nicolar Tablets (Rhone-Poulenc
`Rorer Pharmaceuticals) ...................... 1846
`Slo-Niacin Tablets
`(Upsher-Smith) ............................ 433, 2376
`
`NEOMYCIN SULFATE
`Coly-Mycin S Otic
`w/Neomycin &
`Hydrocortisone (Parke-Davis) ........ 1708
`Cortisporin Cream (Burroughs
`Wellcome) .................................................... 757
`Cortisporin Ointment
`(Burroughs Wellcome) .............................. 758
`Cortisporin Ophthalmic
`Ointment Sterile (Burroughs
`Wellcome) .................................................... 758
`Cortisporin Ophthalmic
`Suspension Sterile
`(Burroughs Wellcome) .............................. 759
`Cortisporin Otic Solution
`Sterile (Burroughs Wellcome) ............. .760
`Cortisporin Otic Suspension
`Sterile (Burroughs Wellcome) .............. 760
`LazerSporin-C Solution
`(Pedinol) .................................................. 1770
`NeoDecadron Sterile
`Ophthalmic Ointment
`(Merck Sharp & Dohmel .................... 1517
`NeoDecadron Sterile
`Ophthalmic Solution (Merck
`Sharp & Dohme) .................................... 1518
`NeoDecadron Topical Cream
`(Merck Sharp & Dohme) .................... 1518
`Neomycin Sulfate Tablets
`(Biocraft) ...................................................... 672
`Neomycin Sulfate Tablets
`(Roxane) .................................................. 1983
`Neosporin Cream (Burroughs
`Wellcome) .................................................... 792
`Neosporin G.U. lrrigant Sterile
`(Burroughs Wellcome) .............................. 793
`Neosporin Ointment
`(Burroughs Wellcome) .............................. 793
`Maximum Strength Neosporin
`Ointment (Burroughs
`Wellcome) .................................................... 793
`Neosporin Ophthalmic
`Ointment Sterile (Burroughs
`Wellcome) .................................................... 793
`Neosporin Ophthalmic
`Solution Sterile (Burroughs
`Wellcome) .................................................... 794
`Neo-Synalar Cream (Syntex) .............. 2296
`PediOtic Suspension Sterile
`(Burroughs Wellcome): ............................. 797
`
`NEOSTIGMINE BROMIDE
`Prostigmin Tablets (ICN
`Pharmaceuticals) .................................. 1121
`
`NEOSTIGMINE METHYLSULFATE
`Neostigmine Methylsulfate
`Injection USP (Apothecon) .................... 601
`Neostigmine Methylsulfate
`Injection (Astra) ...................................... 629
`Neostigmine Methylsulfate
`Injection (Elkins-Sinn) ......................... .-.. 959
`Neostigmine Methylsulfate
`Injection (Geneva Marsam) .............. 1050
`Prostigmin Injectable' aCN
`Pharmaceuticals) .................................. 1120
`
`NETILMICIN SULFATE
`Netromycin Injection 100
`mg/ml (Schering) ................................ 2104
`
`NIACIN
`Nia-Bid Capsules (Geriatric) ................ 1053
`Niacels Capsules (Hauck) .................... 1080
`Niacor Tablets (Upsher-Smith) ............ 2376
`Nicobid (Rhone-Poulenc Rorer.
`Pharmaceuticals) ........................ 427, 1846
`Nicolar Tablets (Rhone-Poulenc
`Rorer Pharmaceuticals) ...................... 1846
`Slo-Niacin Tablets
`(Upsher-Smith) ............................ 433, 2376
`
`Generi-c- and Chemical Name Index
`NORETHYNODREL
`Transderm-Nitro Transdermal
`Therapeutic System
`Enovid 5 mg (Searle) ............................ 2161
`(Summit) ........................................ 432, 2283
`En ovid 1 0 mg (Searle) .......................... 2161
`NITROGLYCERIN INTRAVENOUS
`NORFLOXACIN
`Nitro-Bid IV (Marion Merrell
`Chibroxin Sterile Ophthalmic
`Dow) .......................................................... 1338
`Solution (Merck Sharp &
`Nitrostat IV Ampoules & Vials
`Dohme) .................................................... 1431
`(Parke-Davis) ................................ 422, 1744
`Noroxin Tablets (Merck Sharp
`Nitrostat IV Infusion Kit
`& Dohme) ...................................... 4 19, 1519
`<Parke-Davis) .......................................... 1744
`Tridil Ampuls & Vials (Du Pont
`NORGESTIMATE
`Multi-Source Products) ............................ 939
`Ortho-Cyclen Tablets (Ortho
`Pharmaceutical) .................................... 1658
`NIZATIDINE
`Axid Pulvules (Lilly) ...................... 416,1246 NORGESTREL
`Lo/Ovral Tablets
`NONOXYNOL-9
`(Wyeth-Ayerst) .............................. 436,2471
`Lo/Ovral-28 Tablets
`Semicid Vaginal Contraceptive
`(Wyeth-Ayerst). ............................. 436, 2476
`Inserts (Whitehall) .................... 435, 2422
`Ovral Tablets (Wyeth-Ayerst) .... 436, 2490
`Today Vaginal Contraceptive
`Ovral-28 Tablets
`Sponge (Whitehall) .................... 435, 2422
`(Wyeth-Ayerst) .............................. 436,2491
`Ovrette Tablets (Wyeth-Ayerst) .......... 2492
`NOREPINEPHRINE BITARTRATE
`Levophed Bitartrate Injection
`NORTRIPTYLINE HYDROCHLORI DE
`(Sanofi Winthrop
`Pamelor Capsules (Sandoz
`Pharmaceuticals) .................................. 2054
`Pharmaceuticals) ........................ 427,2019
`NORETHINDRONE
`Pamelor Solution (Sandoz
`Pharmaceuticals) .................................. 2019
`Brevicon 21-Day Tablets
`(Syntex) .......................................... 432, 2304
`NYLIDRIN HYDROCHLORIDE
`Brevicon 28-Day Tablets
`.
`Arlidin Tablets (Rhone-Poulenc
`(Syntex) .......................................... 432, 2304
`Rorer Pharmaceuticals) ...................... 1837
`. Jenest-28 Tablets (Organon) .... 420, 1636
`Nylidrin HCI Tablets (Geneva) ............ 1050
`Micronor Tablets (Ortho
`Pharmaceutical) .......................... 421, 1667
`NYSTATIN
`Modicon 21 Tablets (Ortho
`Mycolog II Cream and
`Pharmaceutical) .......................... 421, 1667
`Ointment (Westwood-Squibb) ............ 2407
`Modicon 28 Tablets (Ortho
`Mycostatin Cream, Ointment,
`Pharmaceutical) .................................... 1667
`Topical Powder
`N.E.E .. 5/35· Tablets (Lexis) .............. 1245
`(Westwood-Squibb) ................................ 2408
`N.E.E. 1/35 Tablets (Lexis). ............... 1245
`Mycostatin Oral Suspension
`N.E.E. 1/50 Tablets (Lexis) ................ 1245
`(Apothecon) ................................................ 605
`N.E.E. 10/11 Tablets (Lexis) ............ 1245
`Mycostatin Oral Tablets
`Nelova (Warner Chilcott) ............... : ...... 2393
`NIFEDIP INE
`(Apothecon) ................................................ 605
`Norethin 1/35E-21
`Adalat Capsules (10 mg and
`Mycostatin Pastilles
`(Schiapparelli Searle) .................. 428,2133
`2 0 mg) (Miles
`·
`(Bristol-Myers Oncology) ............ 406, 734
`Norethin 1/35E-28
`Pharmaceutical) .................. : ....... 420, 1587
`Mytrex Cream & Ointment
`(Schiapparelli Searle) .................. 428,2133
`Nifedipirie Capsules (Warner
`(Savage) .......................................... 427, 2080
`Norethin 1/50M-21
`Chilcott) .................................................. 2393
`Nystatin Oral Suspension,
`(Schiapparelli Searle) .................. 428, 2133
`Procardia Capsules (Pfizer
`USP (Warner Chilcott) ........................ 2393
`Norethin 1/50M-28
`Labs Division) .............................. 423, 1781
`Nystatin Oral Suspension
`(Schiapparelli Searle) .................. 428, 2133
`Procardia XL Extended
`(Biocraft) ...................................................... 672
`Norinyl 1 +35 21-Day
`Release Tablets (Pfizer Labs
`Nystatin Tablets (Par) .......................... 1686
`Tablets (Syntex) .......................... 432,2304
`Division) ........................................ 423, 1783
`Nystatin, USP for
`Norinyl 1 +35 28-Day
`Extemporaneous
`Tablets (Syntex) .......................... 432, 2304
`NIMODIPINE
`Preparation of Oral
`Norinyl 1 +50 21-Day
`Suspension (Paddock) ........................ 1685
`Nimotop Capsules (Miles
`Tablets (Syntex) .......................... 432, 2304
`Pharmaceutical) .......................... 420, 1607
`Norinyl 1 +50 28-Day
`0
`Tablets (Syntex) .......................... 432, 2304
`NITROFURANTOIN
`Norlutin (Parke-Davis) .................. 422, 1755
`Nor-Q D Tablets (Syntex) ............ 432, 2304
`Macrodantin Capsules
`(Norwich Eaton) .......................... 420, 1624
`Ortho-Novum 1/35021
`Tablets (Ortho
`NITROFURANTOIN MACROCRYSTALS
`Pharmaceutical) .......................... 421, 1667
`Ortho-Novum 1/35028
`Macrodantin Capsules
`Tablets (Ortho
`(Norwich Eaton) .......................... 420, 1624
`Pharmaceutical) .................................... 1667
`Ortho-Novum 1/50021
`NITROFURAZONE
`Tablets (Ortho
`Furacin Soluble Dressing
`Pharmaceutical) .......................... 421, 1667
`(Roberts) ........................................ 424, 1854
`Ortho-Novum 1/50028
`Furacin Topical Cream
`Tablets (Ortho
`(Roberts) ........................................ 4 24, 1854
`Pharmaceutical) .................................... 1667
`Furacin Topical Solution
`Ortho-Novum 7/7/7 021
`0.2% (Roberts) .................................... 1855
`Tablets (Ortho
`Pharmaceutical) .......................... 421, 1667
`NITROGLYCERIN
`Ortho-Novum 7/7/7 028
`Deponit NTG Transdermal
`Tablets (Ortho
`Delivery System (Schwarz
`Pharmaceutical) .................................... 1667
`Pharma) .......................................... 429, 2143
`Ortho-Novum 10/11021
`Minitran Transdermal Delivery
`Tablets (Ortho
`System (3M Pharmaceuticals) 416, 1312
`Pharmaceutical) .......................... 4 21,1'667
`Nitro-Bid Ointment (Marion
`.
`Ortho-Novum 10/11028
`Merrell Dow) .............................. : ........... 1339
`Tablets (Ortho
`Nitro-Bid 2.5 Plateau Caps
`Pharmaceutical) .................................... 1667
`(Marion Merrell Dow) ................ 417, 1338
`Ovcon 35 (Mead Johnson
`Nitro-Bid 6.5 Plateau Caps
`Laboratories) ................................ 418, 1391
`(Marion Merrell Dow) ................ 417, 1338
`Ovcon 50 (Mead Johnson
`Nitro-Bid 9 Plateau Caps
`Laboratories) ................................ 418, 1391
`(Marion Merrell Dow~ ................ 417,1338
`Tri-Norinyl 21-Day Tablets
`Nitrodisc (Searle) ............................ 429,2176
`(Syntex) .......................................... 432, 2304
`Nitro-Our (nitroglycerin)
`Tri-Norinyl 28-Day Tablets
`Transdermal Infusion
`.
`(Syntex) .......................................... 432, 2304
`System (Key
`Pharmaceuticals) ........................ 413, 1164
`NORETHINDRONE ACETATE
`Nitrogard Tablets (Forest
`Aygestin Tablets
`Pharmaceuticals) .................................. 1004
`(Wyeth-Ayerst) .............................. 435,2437
`Nitroglycerin S.R. Capsules
`Loestrin ([!] 1/20 (Parke-Davis) 422,1728
`(Geneva) .................................................. 1050 '
`Loestrin ([!] 1.5/30
`Nitroglycerin S.R. Capsules
`(Parke-Davis) ................................ 4 22,·1728
`(Lederle) .................................................. 1192
`Loestrin ~. 1/20 (Parke-Davis) 422,1728
`Nitroglyn Extended Release
`Loestrin ~ 1.5/30
`Capsules (Kenwood) ............................ 1163
`.
`(Parke-Davis) ................................ 422, 1728
`Nitrolingual Spray
`Norlestrin ([!] 1/50
`(Rhone-Poulenc Rorer
`(Parke-Davis) ................................ 4 22,1746
`Pharmaceuticals) ........................ 424, 1846
`Norlestrin ([!] 2.5/50
`Nitrong 2.6 mg. Tablets
`(Parke-Davis) ................................ 4 22,1746
`(Rhone-Poulenc Rorer
`Norlestrin ~ 1/50
`Pharmaceuticals) .................................. 1837
`(Parke-Davis) ................................ 4 22, 1746
`Nitrong 6.5 mg. Tablets
`Norlestrin ~ 2 .5/50
`(Rhone-Poulenc Rorer
`(Parke-Davis) ................................ 422, 1746
`Pharmaceuticals) .................................. 1837
`Norlestrin ~ 1/50
`Nitrostat Tablets (Parke-Davis) 422, 1743
`Transdermai-NTG (Warner
`(Parke-Davis) .......................................... 1746
`Chilcott) .................................................. 2393
`Norlutate (Parke-Davis) ................ 422, 1754
`Italic Page Number Indicates Brief Listing
`
`i
`
`OCTOCRYLENE
`Solbar PF Ultra Cream SPF
`50 (PABA Free) (Person &
`Covey) ...................................................... 1773
`OCTOXYNOL-9
`Massengill Fragrance-Free
`Soft Cloth Towelette
`(SmithKline Beecham
`Consumer Brands) ................................ 219 2
`Massengill Liquid Concentrate
`(SmithKline Beecham
`Consumer Brands) .................. , ....... , ...... 2191
`OCTREOTIDE ACETATE
`Sandostatin Injection (Sandoz
`Pharmaceuticals) ........................ 427,2029
`OCTYL DIMETHYL PABA
`Herpecin-L Cold Sore Lip
`Balm (Campbell) ...................................... 833
`Solbar Plus 15 Cream (Person
`& Covey) .................................................. 1772
`OCTYL METHOXYCINNAMATE
`DML Facial Moisturizer with
`Sunscreen (Person & C:ovey) ............ 1772
`Eucerin Daily Facial Lotion
`(BeiersdorO ................................ : ................. 662
`Purpose Dual .Treatment
`Moisturizer with Sunscreen
`(SPF 12) (Ortho
`Pharmaceutical
`(Dermatological Div.)) .......................... 1680
`Solbar PF 15 Cream (PABA .
`Free) (Person & Covey) ...................... 1772
`Solbar PF 15 Liquid (PABA
`F:ree) (Person & Covey) ...................... 1772
`Solbar PF Ultra Cream SPF
`50 (PABA Free) (Per.son &
`Covey) ...................................................... 1773
`OCTYL SALICYLATE
`Eucerin Daily Facial Lotion
`(BeiersdorO .................................................. 662
`OFLOXACIN
`Floxin Tablets (Ortho
`Pharmaceutical) .................•........ 421, 1652
`OLSALAZINE SODIUM
`Dipentum Caps!Jies (Kabi
`Pharmacia) .............................................. 1160
`
`AMN1040
`IPR of Patent No. 7,919,499
`
`

`

`consult 1992 Supp~ements for revisions
`. g high doses of other antiparkinson drugs. After one to
`1.11 veral weeks at. 100 mg on~e daily, the dose may be in-
`seeased to 100 mg twice daily, if necessary.
`~ccasionally, patients whose responses are not optimal with
`sYMMETREL a~ 2~0 m.g ~aily may benefit from an Increase
`up to 400 mg dail! m diVIded doses. -However; such patients
`should be superVISed closely by their physicians.
`·
`Patients initially deriving benefit from SYMMETREL not
`uncommonly experience a fall-off of effectiveness after a few
`months. B~nefit may b~ regained by .i,ncreasing the dose ~o ·
`aoo mg daily. Altern~tively, ' temporary discont4J.uation of
`sYMMETREL for several weeks, followed by reinitiation of
`the drug, may result in regainilig benefit in some patients. A
`decision to use other antiparkinson drugs may be necessary.
`[)osage for Concomitant Therapy
`Some patients who do not respond to anticholinergic antiparJ
`kinson drugs may respond to SYMMETREL. When SYMME-
`TREL or anticholinergic antiparkinson drugs are each used
`with marginal benefit, concomitant use may produce addi-
`tional benefit.
`When SYMMETREL and levodopa are initi~teP, concur-
`rently, the 'patient can exhibit rapid therapeutic benefits.
`sYMMJITREL should be held _constant at 100 mg daily or
`twice daily ~hile tl).e ~aily ,dose of levodopa is grad '!Ially in-
`creased to optimal benefit.
`.
`When SYMMETREL is added to optimal well-tolerated doses
`oflevodopa, add~tional benefit may result, including smooth-
`ing out the fluctuations in improvement which sometimes
`occur in patients on levodopa alone. Patients who require a
`reduction in their usual dose of levodopa because of develop-
`ment of side effects may possibly regain lost benefit with the
`addition of SYMMETREL.
`Dosage for Drug-Induced Extrapyramidal Reactions:
`Adult: The usual dose of SYMMETREL (amantadine hy-
`drochloride) is 100 mg twice 'a day. Occasionally, patients
`whose responses are nqt optimal with SYMMETREL at 200
`mg daily may benefit from an increase up to 300 mg daily in
`divided doses.
`. .
`'
`Dosage for Prophyl11xis of Influenza A Virus Illness and
`Treatment of Uncomplicated Influenza A Virus Illness:
`Normal Renal Function:
`Adult: The adult daily dosage of SYMMETREL (amanta-
`dine hydrochloride) is 200 mg: two 100 mg capsules (or four
`teaspoonfulS _of syrup) as a single dB.il.y dose, or the daily dos-
`age may be split into one capsule of 100 mg (or two teaspoon-
`fuls of syrup) twice a day. If central nervous system effects
`develop tin once-a-day dosage, a split dosage schedule may
`reduce such complaints'. In persons 65 years of age or older
`the daily dosage of SYMMETREL' is 100 mg.
`'
`Children: , 1 yr.-9 yrs. of age: The total daily dose should be
`calculated on the basis of2 to 4mgllb/day (4.4 to 8.8mg/kg/
`day), but not to exceed 150 mg per day.
`9 yrs.-12 yrs. of age: The total daily dose ls 200 mg given as
`one capsule of 100 mg (or two teaspoonfuls of syrup) twice
`a day.
`Impaired Renal Function: Depending upon creatinine clear-
`ance, the following dosage adjustments are recommended:
`CREATININE
`SYMMETREL
`CLEARANCE
`DOSAGE
`(ml/min./1.73m2)
`- - -
`30-50
`200 mg 1st day and 100 mg
`each day thereafter
`15-29.'
`.200 mg 1st day followed by
`100 mg on alternate days
`< 15
`200 mg every 7 days
`The recm:l!.menaed dosage for patients on hemodialysis is
`200 mg every 7 days.
`.
`~rophylactic dosing should be started in anticipation of im
`~fluenza A outbreak and before or 'after contact with indi-
`= h influenza A vir~s respir~tocy tract illness.
`foU
`.
`EL should be contmued daily for at least 10 days
`owmg a known exposure. If SYMMETREL is used chemo-
`P~ophylactically in conjunction with inactivated influenza A
`~rus . vaccine until protective antibody responses develop,
`. en It should be administered for 2 to 3 weeks after the vac-
`Cine. has. been given. When inactivated influenza A virus
`vhccme IS unavailable or contraindicated, SYMMETREL
`~ ould be administered for up to 90 days in case of possible
`1;~a~ed and unlmown exposures. Treatment of influenza A
`withln illness should be started 'as soon as possible, preferably
`shou 24 to .48 _hours, ~er onset of signs and symptoms, and
`an
`ld be contmued for 24 to 48 hours after the disappear-
`ce of signs and symptoms.
`·
`IIOW SUPPLIED
`.
`~'iMMETREL (amantadine hydrochloride) is available as
`~sules _(each red, soft gelatin capsule contains 100 mg
`Bo antadine hydrochloride) in:
`Bottles of 100 NDC 0056-0105-70
`II tti~s of 500 NDC 0056-0105-85
`Ot~f.~~l Unit-Dose Blister Package of 100 NDC 0056-
`~~ 8Yl'Up (each 5 mL (1 teaspoonful) contains 50 mg aman-
`llle hydrochloride) in:
`
`,
`.
`
`.
`
`Physicians' Desk Ref erence®
`16 oz. (480 mL) bottles NDC'0056-0205-16.·
`Store at controlled room temperature (59~-86•F, 15•-3o•c).
`CAPSULES MANUFACTURED BY
`R.P. Scherer-North America
`St. Pet~rsburg, Florida 33702
`FOR
`Du Pont Pharmaceuticals
`Wilmington, Delaware 19880
`SYMMETREL® is a Registered Trademark of The Du Pont
`Merck Pharmaceutical Co.
`
`6043-21/Rev. June 1988
`
`TREXA N™
`[tr~ks 'an]
`(naltrex.one hydrochloride)
`
`DESCRIPTION
`'!:ey.EXI\N (~altrexone hydrochlor ide), an opioid antagonist,
`IS a synthetic congener of oxymorphone, and is technically,
`therefore, a thebaine derivative. However, it has no opioid
`agonist properties. Naltrexone differs in structure from oxy-
`morphone m t,hat the methyl group on the nitrogen atom is
`replaced by a cyclopropylmethyl group. TREXAN (naltrex-
`one hydrochloride) is also related to the potent opioid antagO-
`nist, naloxone, or n-allylnoroxyillorphone (l'fARCAN®).
`TREXAN (naltrexoQ.e hydrochloride) is' a whi~, crystalline
`compound. The hydrochloride salt is soluble in water to the
`extent of about 100 mg/cc. TREXAN is available in scored·
`tablets containing 50 mg of naltrexone hydrochloride.
`TREXAN Tablets also contain: alginic acid FD&C Yellow 6 '
`microcrystalline cellulose, stearic acid, and sugar.
`'
`CLINICAL PHARMACOLOGY
`Phar~at:~dynamic a.c~ions: TREXAN (naltrexolie hydrO-
`chlonde) IS a pure 9PIOld antagonist. It markedly attenuates
`?r completely blocks, reversibly, the subjective effects of
`~trave~o~~y administered opioids. • [In this context, the
`term op101d IS used to describe 1) Classic moi:phine-like·ago-
`nis~. and 2) analgesics possessing agonist and antagonist
`actiVIty (e.g., butorphanol, nalbuphine and pentazocine).]
`When co-admin~tere~ with morphine, on a chronic basis,
`TREXAN blockS the physical dependence to morph'ine and
`presumably other opioids.
`'
`TREXAN has few, if any, intrinsic actions besides its opioid
`bloc~g properties. However, it does produce some pupillary
`constnctwn,· by an unknown mechanism.
`The administration of TREXAN is not associated with the
`development of tolerance or dependence.
`In subjects physically dependent on opioids TREXAN will
`precipitate withdrawal symptomatology.
`'
`Clinical studies indicate that 50 mg of TREXAN. will block
`the pharmacologic effects of 25 mg of intravenously adminis-
`tered heroin for periods as long as 24 hours. Other data sug-
`gest that doubling the dose of TREXAN provides blockade
`for 48 hours, and tripling the dose of TREXAN provides
`blockade for about 72 hours.
`While the mechanism of actio~· is not fully understood, the
`prepond«;Jrance of evidence suggests that TREXAN blocks
`the effects of opioids by competitive binding (i.e., analogous
`to competitive inhibition of enzymes) at opioid recep-
`tors. This makes the 'Qlockade' produced potentially sur-
`mountable.
`Bio~vailability/Pharmacokinetics: Following oral adminis-
`tration, TREXAN (naltrexone hydrochloride) is subject to
`extensive "first pass" hepatic metabolism (its major route of
`el~ation) witP, approximately 95% of.the absorbed drug
`~emg converted to several metabolites. The major metabo-
`lite, 6-,8-naltrexol, like '!]tEXAN, is believed to be a pure
`antagonist and may contribute to the pharmacological block-
`ade of opioid receptors. A ~or metabolite is 2-hydroxy-
`3-methoxy-6-,8-naltrexol. TREXAN and its metabolites are
`also conjugated to form additional metabolic products.
`T~EXAN. and its metabolites are excreted primarily by the
`kidney, With fecal excretion being a minor elimination path-
`way. The urinary excretion of unchanged TREXAN accounts
`for less than 1% of an oral dose; urinary excretion of un-
`changed and conjugated 6-,8-naltrexol accounts for approxi-
`mately 38% of an oral dose. The pharmacokinetic profile of
`TREXAN suggests that TREXAN and its metabolites un-
`dergo enterohepatic recycling.
`Following the administration of-50 mg TREXAN tablets to
`24 healthy adult male volunteers, the Cmax for TREXAN and
`its major metabolite, 6-,8-naltrexol were 8.6 ng/mL and 99.3
`ng/mL, respectively. The maximum concentration (Cmaxl,
`area under the curve (AUC), and amount excreted in the
`~rine for both TREXAN anq 6-,8-naltrexol increased propor-
`tiOnally as the amount of TREXAN administered increased
`from 50 mg to 200 mg. The time to maximum concentration
`(T maxl is one hour for both T~EXAN and 6-,B~naltrexol. The
`mean elimination half-life (T-%) values for TREXAN and
`6-,8-naltrexol are 3.9 hours and 12.9 hours, respectively. The
`mean elimination half-life (T-%) and time to maximum con-
`centration (Tmaxl for TREXAN and 6-,8-naltrexol are inde-
`pendent of· dose. TREXAN does not accumulate during
`chronic dos~g. As predicted by its longer half-life, plasma
`
`937
`levels of 6-,8-naltrexol increase by 40% during chronic
`TREXAN dosing.
`The total body clearance of TREXAN is 1.5 L/min, which
`approximates liver blood flow, and suggests TREXAN is a
`highly extracted compound. A renal clearance of 127 mL/
`min for TREXAN suggests it is solely cleared by glomerular
`filtration. A renal clearance of 283 mL/min for 6-,8-naltrexol
`suggests an additional renal tubular secretory mechanism.
`The volume of distribution for .TREXAN following intrave-
`nous administration is estimated to be 1350 liters. In vitro
`tests with human plasma show TREXAN to be 21% bound to
`plasma protein, over the therapeutic dose' range.
`In, a relative bioavailability study in 24 healthy adult male
`volunteers, TREXAN tablets were found to be bioequivalent
`to TREXAN syrup; no differences were observed for C
`AUC, an~ urinary excretion .. As expected, the time to m':rii: .
`mum concentration (Tmaxl occurred slightly earlier for the
`syrup (0.6 hours) than for the tablet (1.0 hr).
`INDICATIONS AND USAGE
`.
`TREXAN (naltrexone hydrochloride) is indicated to provide
`~l<!ckade or.~h.e pharmaco~ogic effects qf exogenously a~­
`IStered op101ds as an adJunct to the maintenance of the
`' opioid free-state in 'detoxified formerly opioid-dependent
`individuals.
`~ere are no data that demonstrate an unequivocally benefi-
`Cial effect of TREXAN on rates of recidivism among detoxi-
`fied, formerly opioid-dependent individuals.
`CONTRAINDICATIONS
`TREXAN is contraindica~d in:
`1) Patients receiving opioid analgesics.
`2) Opioid dependent patients.
`3) Patients in acute opioid withdrawal (see WARNINGS).
`4) Any individual who has failed to pass the NARCAN chal-
`lenge (see DOSAGE AND ADMINISTRATION section).
`5) Any individual who has a positive urine screen for opioids.
`6) Any individual with a history of sensitivity to TREXAN
`(naltrexo~e. h!droc~oride). It is not known if there is any
`cross-sensitiVIty With naloxone or other phenanthrene
`containing opioids.
`'
`7) Any individual with •acute hepatitill or liver failure.
`WARNINGS
`Hepatotoxicity:
`
`TREXAN has the capacity to cause dose related hepato-
`cellular injury.
`.
`Prior to making a decision to initiate treatment with
`TREXAN, the physician should estabiish whether the
`patient has subclinical liver injury or disease. (See PRE-
`CAUTIONS; Laboratory Tests.) TREXAN is contraindi-
`cated in acute hepatitis or liver failure, but its use even
`in patients with evidence of less severe liver disease or a
`history of recent liver disease must be carefully consid-
`ered in light t;~f its hepatotoxic potential.
`The evidence that. identified TREXAN as a hepatotoxin
`was not obtained in studies involving its use at the
`doses recommended for opiate blockade, where the
`changes in serum levels of liver enzymes seen were simi-
`lar to those present at baseline in the study population.
`However, the margin of separation between the appar-
`ently safe and the hepatotoxic doses appears to be only
`five-fold or less.
`·
`.
`
`Evi~ence of TREXAN's hepatotoxic potential is derived pri-
`marily from a placebo controlled study in which TREXAN
`was administered to _obese subjects at a dose approximately
`five-fold that recommended for the blockade of opiate recep-
`torS' (300 mg per day). In the study, 5 of 26 TREXAN recipi-
`ents developed elevations of serum transaminases (i.e., peak
`SGPT values ranging from a low of 121 to a high of 532· or 3
`to 19 times their baseline values) after three to eight V.:eeks
`0~ t~eatment. Althoug~ the patients mvolved were generally
`clinically asymptomatic and the transaminase levels of all
`patients on whom follow-up was obtained returned to (or
`toward) baseline values in a matter of weeks, the lack of any
`transaminase elevations of similar magnitude in any of the
`24 placebo pati~nts in the same s.tudy is persuasive evidence
`tha~ TRE?CAN IS a ~re~t (i.e., not an idiosyncratic) hepato-
`to~. This conclusiOn IS also supported by evidence from
`other plac.ebo ~ontrolled studies in which exposure to
`TREXAN at doses froin one to two-fold the amount recom-
`mended for opiate blockade consistently produced more nu-
`merous and more significant elevations of serum transami-
`nases than did placebo, and reports of transaminase eleva-
`tions in 3 of 9 patients with Alzheimer's Disease who re-
`ceived TREXAN (up to 300 mg/day) for 5 to 8 weeks in a open
`clinical trial.
`Unintended Precipitation of Abstinence: To prevent occur-
`rence of an acute abstinence syndrome, or exacerbation of a
`pre-e)!:isting sub-clinical abstinence syndrome, patients
`should remain opioid-free for a minimum of 7-10 days before
`starting TREXAN. Since the absence of an opioid drug in the
`
`Continued on next page
`
`AMN1040
`IPR of Patent No. 7,919,499
`
`

`

`938
`DuPont Multi-Source-Cont.
`
`urine is often not sufficient proof that a patient is opioid-free,
`a NARCAN challenge should be employed to exclude the
`possibility of. precipitating a withdrawal reac~ion following
`administration of TREXAN. The NARCAN challenge test is
`described in the DOSAGE AND ADMINISTRATION section.
`While TREXAN is a potent antagonist with a prolonged
`pharmacologic effect (24 to 72 hours), the blockade produced .
`by TREXAN is surmountable. This is useful in patients who
`may require analgesia, but poses a potential risk to individu-
`als who attempt, on their own, to overcome the blocitade by
`administering large amounts of e