REFERENCE
`
`PHYSICIANS’
`nian
`
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:40)(cid:59)(cid:43)(cid:44)(cid:37)(cid:44)(cid:55)(cid:3)(cid:20)(cid:19)(cid:20)(cid:26)
`(cid:36)(cid:83)(cid:82)(cid:87)(cid:72)(cid:91)(cid:3)(cid:89)(cid:17)(cid:3)(cid:36)(cid:79)(cid:78)(cid:72)(cid:85)(cid:80)(cid:72)(cid:86)(cid:3)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:24)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:23)
`
`

`

`
`
`PDR
`53
`
`EDITION
`
`1999
`
`PHYSICIANS
`DEK
`REFERENCE
`
`
`
`
`
`
`
`
`.
`Medical Consultant
`
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`
`Vice President of Directory Services: Stephen B. Greenberg
`Director of Product Management: David P. Reiss
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Senior Product Manager: Mark A. Friedman
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Associate Product Manager: Bill Shaughnessy
`Editor, Special Projects: David W. Sifton
`Director of Sales: Dikran N. Barsamian
`Vice President of Production: David A. Pitler
`National Sales Manager: Anthony Sorce
`Director of Print Purchasing: Marjorie A. Duffy
`National Account Manager: Don Bruccoleri
`Director of Operations: Carrie Williams
`Account Managers:
`Managerof Production: Kimberly H. Vivas
`Marion Gray, RPh
`Senior Production Coordinators: Amy B. Brooks, Dawn McCall
`Lawrence C. Keary
`Production Coordinator: Mary Ellen R. Breun
`Jeffrey F. Pfohl
`PDR Data Manager: Jeffrey D. Schaefer
`Christopher N. Schmidt
`Stephen M. Silverberg
`Senior Format Editor: Gregory J. Westley
`Suzanne E. Yarrow, RN
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`National Sales Manager, Trade Group:Bill Gaffney
`Art Associate: Joan K. Akerlind
`Director of Direct Marketing: Michael Bennett
`‘Senior Digital Imaging Coordinator: Shawn W. Cahill
`Direct Marketing Manager: Lorraine M. Loening
`Digital Imaging Coordinator: Frank J. McElroy, III
`Promotion Manager: Donna R. Lynn
`Electronic Publishing Designer: Robert K. Grossman
`Director, Professional Support Services: Mukesh Mehta, RPh
`Fulfillment Managers: Stephanie DeNardi, Kenneth Siebert
`
`
`’
`
`aes Copyright @ 1999 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. Noneof the contentof,this publication
`a may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means(electronic, mechanical, photocopying, record -
`ing, or otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR”, POR For Nonprescription Drugs’, PDR For
`Ophthalmology", Pocket PDR", and The POR” Family Guide to Prescription Drugs® are registered trademarks used herein underlicense, PDR Companion Guide™,
`PDR* for Herbal Medicines™, PDR” Medical Dictionary™, PDR” Nurse's Handbook™, PDR® Nurse's Dictionary™, The PDR® Family Guide Encyclopedia of Medical
`Care™, PDR®* Electronic Library™, and PDR®Drug Interactions, Side Effects, Indications, Contraindications System™are trademarks used herein underlicense.
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate
`Human Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Senior Vice President, Finance, and Chief Financial Officer: Thomas
`W. Ehardt; Vice President, Directory Services; Stephen B. Greenberg; Vice President, New Business Planning: Linda G. Hope; Executive Vice President, Healthcare Publishing
`and Communications: Thomas J. Kelly; Executive Vice President, Magazine Publishing: Lee A. Maniscalco; Vice President, Group Publisher: Terrence W. Meacock; Vice
`President, Production: David A. Pitler; Vice President, Group Publisher: Thomas C. Pizor; Vice President, Magazine Business Management:Eric Schlett; Senior Vice President,
`Operations: John R. Ware
`
`® Printed on recycled paper
`
`'
`
`ISBN: 1-56363-288-8
`
`

`

`REVIA®
`lreh. “vee "uh "]
`(naltrexone hydrochloride tablets)
`
`B
`
`
`
`Irvine, CA USA 92614-5895
`6270-3/Rev, November, 1997
`PENTASPAN® and HESPAN®are registered
`trademarks of
`The DuPont Merck Pharmaceutical Co.
`
`DESCRIPTION:
`neVia (naltrexone hydrochloride), an opioid antagonist, is a
`synthetic congener of oxymorphone with no opioid agonist
`properties, Naltrexone differs in structure from oxymor-
`phone in that the methyl group on the nitrogen atom is re-
`placed bya cyclopropylmethyl group. reVia is also related to
`the potent’opioid antagonist, naloxone, or n-allylnoroxymor-
`phone [NARCAN® (naloxone hydrochloride),
`
`
`936/DUPONT PHARMA
`PHYSICIANS’ DESK REFERENCE®
`
`
` 5 to 40%. The activity of naltrexone is believed to be due to
`There are no data that demonstrate an unequivocally ben-
`Pentaspan—Cont.
`both parent and the 6-8-naltrexol metabolite. Both parent
`eficial effect of neViA on rates of recidivism among detoxi-
`drug and metabolites are excreted primarily by the kidney
`fied, formerly opicid-dependentindividuals who self-admin-
`ommended that the product be stored at room temperature
`(53% to 79% of the dose), however, urinary excretion of un-
`ister the drug, The failure of the drug in this setting ap-
`(25°C); however, brief exposure up to 40°C does not ad-
`pears to be due to poor medication compliance,
`changed naltrexone accounts for less than 2% of an oral
`versely affect the product.
`dose and fecal excretion is a minor elimination pathway,
`‘The drug is reported to be of greatest use in good prognosis
`Caution: Federal (JSA) law prohibits dispensing without
`The niean elimination half-life (T-1/2) values for naltrexone
`opioid addicts who take the drug as part of a comprehensive
`prescription.
`and 6-B-naltrexol are 4 hours and 13 hours, respectively,
`occupational rehabilitative program, behavioral contract, or
`Distributed by;
`Naltrexone and 6-f-naltrexol are dose proportional in terms
`other compliance-enhancing protocol. neVia, unlike metha-
`DuPont Pharma
`ofAUC andC,,,, over the range of 50 to 200 mg and do not
`done or LAAM (levo-alpha-acetylmethadol), does not rein-
`Wilmington, Delaware 19880
`accumulate after 100 mz daily doses,
`force medication compliance and is expected to have a ther-
`Absorption
`apeutic effect only when given under external conditions
`that support continued use of the medication.
`Following oral administration, naltrexone undergoes rapid
`Individualization of Dosage:
`and nearly complete absorption with approximately 96% of
`the dose absorbed from the gastrointestinal tract. Peak
`DO NOT ATTEMPT TREATMENT WITH reVia UNLESS,
`IN THE MEDICAL JUDGEMENT OF THE PRESCRIBING
`plasma levels of both naltrexone and 6-f-naltrexol occur
`PHYSICIAN, THERE 15 NO REASONABLE POSSIBILITY
`within one hour of dosing.
`OF OPIOID USE WITHIN THE PAST 7-10 DAYS. IF
`;
`Distribution
`The volumeofdistribution for naltrexone following intraye-
`THERE IS ANY QUESTION OF OCCULT OPIOID DE-
`nous administration is estimated to be 1360liters. In vitro
`PENDENCE, PERFORM A NARCAN CHALLENGE. TEST,
`Treatment of Alcoholism:
`tests with human plasma show naltrexone to be 21% bound
`The placebo-controlled studies that demonstrated the effi-
`to plasma proteins over the therapeutic dose range.
`Metabolism
`cacy of neVia as an adjunctive treatment of alcoholism used
`a dose regimen of neVia (naltrexone hydrochloride) 60 mg
`The systemic clearance (after intravenous ddnntnintration)
`once daily for up to 12 weeks. Other dose regimens or dura-
`of naltrexone is -~3.5 L/min, which exceeds liver blood flow
`tions of therapy were not studied in these trials;
`(~1.2 L/min). This suggests both that naltrexoneis a highly
`extracted drug (>98% metabolized) and that extra-hepatic
`Physicians are advised that §-15% of patients taking REViA
`for alcoholism will complain of non-specific side effects,
`sites of drug metabolism exist. The major metabolite of nal-
`trexone is 6-A-naltrexol, Two other minor metabolites are
`chiefly gastrointestinal upset. Prescribing physicians have
`tried using an initial 25 mg dose, splitting the daily dose,
`2-hydroxy-3-methoxy-6-f-naltrexol and 2-hydroxy-3-meth-
`and adjusting the time of dosing with limited success, No
`yl-naltrexone. Naltrexone and its metabolites are also con-
`dose or pattern of dosing has been shown to be more effec-
`jugated to form additional metabolic products.
`tive than any other in reducing these complaints for al] pa-
`Elimination
`tients.
`‘The renal clearance for naltrexone ranges from 30-127 mL/
`Treatment of Opioid Dependence:
`min and suggests that renal elimination is primarily by glo-
`Once the patient has been started on neVia, 60 mg once.a
`merular filtration. In comparison, the renal clearance for
`day will produce adequate clinical blockadeofthe actions of
`6-f-naltrexol ranges from 230-369 mL/min, suggesting an
`parenterally administered opioids. As with many non-ago-
`additional renal tubular secretory mechanism. The urinary
`nist treatments for addiction, reVia is of proven value only
`excretion of unchanged naltrexone accounts for less than
`N-CH;—<"
`when given as part of a comprehensiveplan ofmanagement
`2% of an oral dose; urinary excretion ofunchanged and con-
`that includes some measure to ensure the patient takes the
`* HCI
`jugated 6-f-naltrexol accounts for 43% of an oral dose. The
`medication.
`pharmacokinetic profile of naltrexone suggests that naltrex-
`nallraxone hydrochloric
`A flexible approach to a dosing regimen may be employed to
`one and its metabolites may undergo enterohepati¢ recy-
`compliance, Thus, patients may receive 50 mg of
`cling.
`aeVia is a white, crystalline compound. The hydrochloride
`salt is soluble in water to the extent of about 100 mg/mL,
`Hepatic and Renal Impairment
`REVIA every weekday with a 100 mg dose on Saturday or
`patients may receive 100 mg every other day, or 150 mg ev-
`neVia is available in scored film-coated tablets containing 50
`Naltrexone appears to have extra-hepatic sites of drug me-
`ery third day. Several of the clinical studies reported in the
`mg of naltrexone hydrochloride
`tabolism and its major metabolite undergoes active tubular
`literature have employed the following dosing regimen: 100
`reVia Tablets also contain: lactose, microcrystalline cellu-
`secretion (see Metabolism above), Adequate studies of nal-
`mg on Monday, 100 mg on Wednesday, and 150 mg on Fri-
`lose, crospovidone,- colloidalsilicon dioxide, magnesium
`trexone in patients with severe hepatic or renal impairment
`day. This dosing schedule appeared to be acceptable to
`stearate, hydroxypropyl methylcellulose, titanium dioxide,
`have not been conducted (gee PRECAUTIONE: Special
`manyR&VIA patients successfully maintaining their opiaid-
`polyethylene glycol, polysorbate- 80, yellow iron oxide and
`free state.
`RiskPatients).
`red iron oxide.
`Clinical Trials:
`Experience with the supervised administration of a number
`Alcoholism:
`CLINICAL PHARMACOLOGY:
`of potentially hepatotoxic agents suggests that supervised
`Theefficacy of REVIA as an aid to the treatment of alcoholism
`Pharmacodynamic Actions: neVia is a pure opioid antago-
`administration and single doses of neVia higher than 50 mg
`was tested in placebo-controlled, outpatient, double blind
`nist. It markedly attenuates or completely blocks, revers-
`may have'an associated increased risk of hepatocellular in-
`trials, These studies used a dose of neVia 50 mg once daily
`ibly, the subjective effects of intravenously administered
`jury, even|though three-times a week dosing has been well
`for 12 weeks as an adjunct to social and psychotherapeutic
`opioids,
`tolerated in the addict population’ andin initial clinical tri-
`methods when given under conditions that enhanced pa-
`When co-administered with morphine, on a chronic basis,
`als inalcoholism. Clinics using this approach should bal-
`tient compliance. Patients with psychosis, dementia, and
`aeVia blocks the physical dependence to morphine, heroin
`ance the possible risks against the probable benefits and
`secondary psychiatric diagnoses were excluded from these
`and other opioids.
`may wish to maintain a higher index of suspicion for drug-
`studies.
`neVis has few, if any, intrinsic actions besides its opioid
`associated hepatitis and ensure patients are advised of the
`In one of these studies, 104 alcohol-dependent patients were
`blocking properties. However, it does produce some pupil-
`need to report non-specific abdominal complaints (see In-
`randgmized to receive either reViA 60 mg once daily or pla-
`formation for Patients).
`7
`lary constriction, by an unknown mechanism.
`cebo. In this study, xeVia proved superior to placebo in
`The administration of neViA is not associated with the de-
`INDICATIONS AND USAGE:
`measures of drinking including abstention rates (51% vs.
`velopmentoftolerance or dependence. In subjects physically
`reVia is indicated :
`23%), number of drinking days, and relapse (31%. vs. 60%).
`dependent on opioids, reVia will precipitate withdrawal
`In the treatment of aleohol dependence and for the blockade
`In a second study with 82 alcohol-dependent patients, the
`symptomatology.
`of the effects of exogenously administered opioids.
`group ofpatients receiving xEViA were shown to have lower
`Clinical studies indicate that 50 mg of neVia will block the
`reVia has not been shown to provide any therapeutic benefit
`pharmacologic effects of 25 mg of intravenously adminis-
`relapse rates. (21% vs, 41%), less alcoholcraving, and fewer
`except as part of an appropriate plan ofmanagementfor the
`drinking days compared with patients ‘who received pla-
`tered heroin for periods as long as 24 hours. Other data sug-
`addictions,
`gest that doubling the dose of neVia provides blockade for 48
`cebo, but these results depended on the specific analysis
`ued.
`hours, and tripling the dose of reVia provides blockade for
`CONTRAINDICATIONS:
`about 72 hours.
`REV1A is contraindicated int
`The clinical useof reVia as adjunctive pharmacotherapy for
`the treatmentofalcoholism was also evaluatedin a multi-
`reVia blocks the effects, of opioids by’competitive binding
`1), Patients receiving opioid analgesics.
`center safety study, This study of 865 individuals with alco-
`(ie., analogous to competitive inhibition of enzymes) at
`2) Patients currently dependenton opisids,
`3) Patients.in acute opioid withdrawal (see WARNINGS).
`opioid receptors. This makes the blockade produced poten-
`holism included patients with comorbid psychiatric condi-
`tions, concomitant medications, polysubstance abuseand
`tially surmountable, but overcoming full naltrexone block-
`4) Any individual who. has failed the NARCANchallenge
`HIV. disease, Results of this study demonstrated that the
`ade by administration of very high doses ofopiates has re-
`test: or who has,a positive urine screen for opioids,
`side effect: profile ofREVIA appears to. be similar in both al-
`sulted in excessive symptoms of histamine release in exper-
`5) Any individual with ‘a history of sensitivity to reViA or
`imental subjects.
`coholicand opioid dependent populations, and that serious
`any other components ofthis product. It is not known if
`side effects are uncommon,
`The mechanism ofaction of xsVia in alcoholism is not-un-
`there is. any cross-sensitivity with naloxone or the phe-
`In the ¢linical studies, treatment with reViA supported ab-
`derstood; however, involvement of the endogenousopioid
`nanthrene containing opioids.
`stinence, prevented relapse and decreased alecho! consump-
`system is suggested by preclinical data.reVia, an opioid re-
`6) Any individual with acute hepatitis orliver failure.
`tion. In the uncontrolled study, the patterns of abstinence
`ceptor antagonist, competitively binds to such receptorsand
`WARNINGS:
`and relapse were similar to those observed in the controlled
`mayblock the effects of endogenous opioids, Opioid antago-
`Hepatotoxicity:
`studies. REViA was not uniformly helpful to all patients, and
`nists have been shown to reduce alechol consumption by
`
`the expected effect of the drng is a modest improvementin
`animals, andreVia has been shown to reduce alcoholcon-
`the outcome of conventional. treatment.
`sumption in clinical studies,
`reVia.has the capacity to. cause hepatocellular. injury
`Treatment of Opioid Addiction:
`REVIA is not aversive therapy ‘and does not cause a disulfi-
`when given in excessive doses,
`tam-like reaction either as a result of opiate use or ethanol
`neVis has been shown to produce complete blockadeof the
`neVid is contraindicated in acute hepatitis or fiver fail-
`ingestion,
`euphoric effects of opioids in both volunteer and addict
`ure, and-its use in patients with active liver disease
`Pharmacokinetics
`populations.. When administered by means that enforce
`must becarefully considered jn light of its hepatotoxte -
`effects,
`neVia is a pure opioid receptor antagonist. Although well ab-.
`compliance,it will produce an effective opioid blockade, but
`has not been shown to affect the use of cocaine or other non-
`sorbed orally, naltrexone is subject: to significant first pass
`The margin of separation between the apparently safe
`metabolism with oral bioavailability estimates ranging from
`opicid drugs of abuse,
`dose of reViA and the dose causing hepatic injury ap-
`Information will be superseded by supplements and subsequent editions
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PRODUCT INFORMATION
`
`i pears to be only five-fold or less. reViA does not appear
`| tobea hepatotoxin at the recommended doses.
`~
`
`patients should be warned of the risk ofhepatic injury
`| and advised to stop the use of neVia and seek medical.
`
`“attention if they experience symptoms ofacute hepa-
`
`
`
`Byidence ofthe hepatotoxic potential ofneViaisderivedpri-
`
`‘marily from a placebo controlled study in which neViA was
`
`
`4
`inistered to obese subjects at a dose approximately five-
`fold that recommended for the blockade ofopiate receptors
`(g00mg per day). Inthat study, 5 of 26 reViA recipients de-
`
`
`‘veloped elevations of serum transaminases(i.e., peak ALT
`“yalues ranging from a low of 121 to ahigh of 532; or 8 to 19
`
`
`times their baseline yalues) after three to eight weeks of
`freatment, Although the patients involved were generally
`
`
`‘clinically asymptomatic and the transaminase levels ofall
`
`
`patients on whom follow-up Was obtained returnedto (or to-
`ward) baseline values in a miatter ofweeks,the lackof any
`
`
`transaminase elevations of similarmagnitude in-any of the
`94placebo patients in the same study is persuasive evi-
`‘dence that neVia is a direct (ie.; nat idiosyncratic) hepato-
`PFetaclusion is also supported by evidence from other.
`Jucebo controlled studies in which exposure to neViA at
`‘doses above the amount recommended for the treatment of
`alcoholism or opiate blockade (50 mg/day) consistently pro-
`duced more numerous and more significant elevations of
`serum transaminases than did placebo. Transaminaseel-
`syations in 3 of 9 patients with Alzheimer’s Disease who re-
`rivedneVia (at doses up to 300 mg/day) for 5 to 8 weeks in
`‘an open clinical trial have bean reported.
`:
`Although no cases of hepatic failure due to seVia adminis-
`tration have ever been reported, physicians are advised 'to
`‘consider this as a possible risk of treatment and to tise the
`‘gamecare in prescribing neVia as they would other drugs
`with the potential for causing hepatic injury.
`Unintended Precipitation of Abstinence:
`Toprevent occurrence of an acute abstinence syndrome,or
`exacerbation of a pre-existing stbclinical abstinence syn-
`drome, patients must be opioid-free for a minimum of 7-10
`days before starting-ReVia. Since the absence of an opioid
`drug in the urine is often not sufficient proof that a patient
`‘is opioid-free, a NARCAN challenge should be employedif
`the prescribing physician feels there is a risk of precipitat-
`ing @ withdrawal reaction followingadministration of ne-
`Vu The NARCAN challenge test is described inthe DOS-
`AGE AND ADMINISTRATIONsection,
`"
`.
`Attempt to Overcome Blockade:
`While reVia is a potent antagonist with a prolonged phar-
`imiscalogic effect (24 to 72 hours), the blockade produced by
`eVia is surmountable. This is useful in patientswho m:
`require analgesia, but poses a potential risk to individuals
`who attempt, on their own,to overcomethe blockadeby ad-
`ministering large amounts of exogenous opioids, Indeed,
`any attempt by a patient to overcome the antagonism by
`taking opioids is very dangerous and may lead to a fatal
`‘overdose. Injury may arise because the plasma concentra-
`lion of exogenous: opioids attained immediately following
`their acute administration may be sufficient to overcome the
`Competitive receptor blockade. As a consequence, the pa-
`tient may be in immediate danger of suffering life endan-
`fenng opioid intoxication (e.g., respiratory arrest, circula-
`tory collapse), Patients should be told of the serious conse-
`fugnees of trying to overcome the opiate blockade (See
`i
`ition for Patients),
`:
`There is also the possibility that a patient who had been
`treated with naltrexone will respond to lower doses of opia-
`‘ids than previously used, particularly if taken in such a
`Manner that high plasma concentrations remain in the body
`beyond the time that naltrexone’ exerts its therapeutic ef-
`fects,This could result in potentially life-threatening opioid
`tion (respiratory compromise or arrest, circulatory
`collapse, ete,), Patients should be aware that they may be
`more sensitive to lower
`doses of opioids
`naltrexone
`treatmentis discontinued.
`Ultra Rapid Opioid Withdrawal:
`Sale use of zeVia in ultra rapid opiate detoxification pro-
`TON
`not been established (see ADVERSE REAC-
`PRECAUTIONS: General
`When Reversal of reViA Blockade is Required: In an emer-
`Eebcy situation in patients receiving fully blocking doses of
`NEVA, 2 suggested plan of managementis regional analge-
`"8, conscious sedation with a benzodiazepine, use ofnon-
`a analgesics or general anesthesia.
`4 situation requiring opioid analgesia, the amount of
`Spioid Tequired may be greater than usual, and the result-
`ing oentoy depression may be deeper and more pro-
`A rapidly aeting opioid analgesic which minimizes the du-
`ration ofrespiratory depression ispreferred. The amount of
`the
`ic administered should be titrated to the needs of
`Patient, Non-receptor mediated actions may occur and
`
`DUPONT PHARMA/937
`
`should be expected(e.g., facial swelling, itching, generalized
`tered to a patient receiving neViA, the amount of opioid
`erythema, or bronchoconstriction) presumably due to hista-
`required may be greater than usual, and the resulting res-
`mine release,
`f
`piratory depression may be deeper andmore prolonged (see
`PRECAUTIONS).
`Irrespective of the drug chosen to reverse reVia blockade,
`the patient should be monitored closely by appropriately
`Carcinogenesis, Mutagenesis and Impairment of Fertility:
`Carcinogenicity studies in rats and mice were conducted at
`trained personnel in a setting equipped and staffed for car-
`diopulmonary resuscitation.
`:
`doses as high as 100 times the human dose, There was no
`Accidentally Precipitated Withdrawal: Severe opioid with-
`statistically significant increasein the incidenceof any tu-
`drawal syndromes precipitated by the accidental ingestion
`mors and, except for vascular tumors in the neVia-treated
`female rats, the incidence of tumors observed in the studies
`ofneViahave been reported in opioid-dependent individuals.
`Symptoms of withdrawal have usually appeared within five
`were within ranges seen in historical control groups. rEVIA
`“ininwtes ‘of-ingestion of reViA.and have lasted for upto 48
`was negative in bacterial and cultured mammalian cell mu-
`hours. Mental status changes including confusion, somno-
`tation, in vitro chromosome aberration, and in vive micro-
`lence and visual hallucinations have occurred. Significant
`nucleus, chromosome aberration, and heritable transloca-
`fluid losses from vomiting and diarrhea have fequired intra-
`tion assays. It was weakly positive in the Drosophila mela-
`venous fluid administration. In all cases patients were
`nogaster recessive lethal test and gave equivocal responses
`in £. coli DNA repair and in in vitro mammalian cell muta-
`closely monitored and therapy with non-opioid medications
`was tailored to mect individual requirements,
`-
`tion and anaphase chromosome assays. Overall, the study
`Use of neViA does not eliminate or diminish withdrawl
`results indicate that the genotoxic potential of reVia is low.
`symptoms, If REViAis initiated early in the abstinence pro-
`geVia (100 mg/kg, approximately 100 times the human ther-
`cess, it will not precludé the patient's experience of the full
`apeutic dose) caused an increase in pseudopregnancy and a
`decrease in the pregnancy rates of female rats, Therele-
`range of signs and symptoms that would be experienced if
`vance to these observations to human fertility ia not known.
`reVia had not been started. Numerous adverse events are
`Pregnancy: Category.C.° - xeVia has beenshown to have em-
`known to be associated with withdrawal.
`Special Risk Patients:
`bryocidal and fetotoxic effects in rats and rabbits when
`Renal Impairment:
`seViA and its primary metabolite are
`given in dosages 30 and 60 times, respectively, the human
`dose,
`o
`bw
`excreted primarily inthe urine, and caution is recom-
`There are no adequate and well-controlled studies in preg-
`mended in sdministering the drug to patients with renal
`impairment.
`nant women. reVis should be used in pregnancy only when
`the potentialbenefit justifies the potential riskto the fetus.
`Hepatic Impairment: Cautions should be exercised when
`Labor and Delivery: Whether or not reVia affects the du-
`naltrexone hydrochloride is administered to patients with
`liver disease, An increase in naltrexone AUC of approxi-
`rationof laboriand delivery is unknown.
`Nursing Mothers: Whether or not reViv is excreted in hu-
`mately 5- and10-fold in patients with compensated and dec-
`man milk is unknown..Because many drugs are excreted in
`ompensated liver cirrhosis, respectively, compared with sub-
`human milk, caution should be exercised when neVia is ad-
`jects with normal liver function has been reported. These
`ministered to a nursing woman.
`data also suggest that alterations in naltrexone bioavail-
`ability are related to liver disease severity.
`Pediatric Use:
`The safe use ofxeVia in pediatric patients
`Suicide: The risk of suicide is known to be increased in
`younger than 18 years old has‘not: been established,
`patients with substance abuse
`with orwithout concomitant
`
`ADVERSE REACTIONS:
`;
`depression, This risk is not abated by treatment with neVia
`(see ADVERSE REACTIONS).
`During two. randomized, double-blind placeho-controlled 12
`week trials to evaluate the efficacy ofneVia as an adjunctive
`Information for Patients:
`It is recommended thatthe pre-
`treatmentof alechol dependence, most patients tolerated re-
`scribing physician relate the following information to pa-
`Via well. In these studies, a total of 98 patients received az-
`tientsbeing treated with mkVia:
`:
`Via at a dose of60 mg once daily. Five of these patients dis-
`You have been, prescribed xeVia as ‘part of the comprehen-
`continued neVia because of nausea. No serious adverse
`sive treatmentfor your alcoholism or drug dependence. You
`events were reported during these two trials,
`should carry identification to alert medicalpersonnel to the
`While extensive clinical studies evaluating the use of neVia
`factthat you ate taking reVia (naltrexone hydrochloride), A
`in detoxified, formerly opicid-dependent individuals failed
`neVia medication card may be obtained from your physician
`to identify any single,serious untoward risk of reViA use,
`‘and can be used for this purpose. Carrying the identification
`placebo controlled studies employing up to five-fold higher
`card should help to ensure that youcan obtain adequate
`doses of neVia (up to 300 mg per day) than that recom-
`treatment in an emergency, If you require medlical treat
`mended for use in opiate receptor blockade have shown that
`ment, besure {o tell thetreating physician that you are re-
`nEViA causes hepatocellular injury in a substantial propor-
`ceiving REViA therapy,
`:
`tion of patients exposed at higher doses (see WARNINGS
`You shouldtake keViAas directedby your physician. If you
`and PRECAUTIONS: Laboratory Tests).
`5
`attempt to self-adininister heroin or any other opiate drug,
`Aside from this finding, and the risk of precipitated opinid
`in emall doses while re reViA, youwill not prea > ef-
`withdrawal; available evidence does not incriminate nEeVia,
`fect. Most important,
`however, if you attempt to self-admin-
`‘statTagsdoes of heroin or any other opioid While on HE-
`used at any dose, as a cause of any other serious adverse
`VIA,
`you
`die or sustain serious inj
`including
`coma,
`reaction for the patient who is “opioid free.” Tt is critical to
`aEVIA is well-tolerated inthe ener| doses, but may
`recognize that reViA can precipitate or exacerbate absti-
`hence signs and symptoms in any individual who is not com-
`cuse liver injury when taken ‘in excess or in people’ who
`pletely free. of exogenous opioids.
`:
`develop liver disease from other causes. If you develop ab-
`Patients with addictive disorders, especially opioid addic-
`dominal pain lasting more than a few days, white bowel
`tion, are at risk for multiple numerous adverse events and
`movements, dark urine, or yellowing of your eyes, you
`abnormal. laboratory findings, including
`liver function ab-
`should stop takingHEViA immediately and see your doctor as
`normalities, Data from both controlled and observational
`soon aspossible.
`,
`ed
`studies suggest that these abnormalities, other than the
`Laboratory Tests:
`A high index of suspicion for drug-
`dose-related hepatotoxicity described above, are not related
`related hepatic injury is critical if the occurrence ofliver
`to the use of neVin.
`-
`damage induced byneVia is to be detected at the earliest
`Amongopioid free individuals, xeVis administration at the
`possible time. Evaluations, using appropriate batteries of
`recommended dose has not been associated with a predict-
`tests to detect liver injury are recommendedat a frequency
`able profile ofserious adverse or untoward events, However,
`appropriate to the clinical situation and thedose ofreVia.
`as mentioned above, among individuals usingopioids, neViA
`reVia does not interfere with thin-layer, gas-liquid, and high
`may cause serious withdrawal reactions (see CONTRAIN-
`pressure liquid chromatographic methods which may be
`DICATIONS, WARNINGS, DOSAGE AND ADMINIS-
`used for the separation and detection of morphine, metha-
`TRATION).
`doneor quinine in thetirine, xeVia may or may not interfere
`Reported Adverse Events
`with enzymatic methods for the detection ofopioids depend-
`reVia has not been shown to cause significant increases in
`ing on the specificity of the test. Please consult the test
`complaints in placebo-controlled trials in patients known to
`manufacturer for specific details.
`be free of opioids for more than 7-10 days. Studies in alco-
`Drug Interactions:
`Studies to evaluate possible interac-
`holic populations and in volunteers in clinical
`logy
`tions between reVia and drugs other than opiates have not
`studies have suggested that a small fraction of patients may
`been performed. Consequently, caution is advised if the con-
`experience an opioid withdrawal-like symptom complex con-
`comitant administrationof neVi and other drugs is re-
`q
`“
`sisting of tearfulness, mild nausea, abdominal cramps,rest-
`lessness, bone or joint pain, myalgia, and nasal symptoms.
`The safety and efficacy of concomitant use of neVia and di-
`sulfiram is unknown, and the concomitant use of two poten-
`This may represent the unmasking ofoccult opioid use, or it
`may represent symptoms attributable to naltrexone. Anum-
`tially hepatotoxic medications is not ordinarily recom-
`ber of alternative dosing patterns have been recommended
`mended unless the probable benefits outweigh the known
`risks.
`to try to reduce the frequency of these complaints (see In-
`dividualization of Dosage),
`Lethargy and somnolence have been reported following
`Alcoholism:
`doses of reVia and thioridazine.
`Patients taking reViA may not benefit from opioid contain-
`Tn an open label safety study with approximately 570 indi-
`ing medicines, such as cough and cold preparations, antidi-
`viduals with alesholism receiving seVia, the following new-
`arrheal preparations, and opioid analgesics. In an emer-
`Continued on next page
`gency situation when opioid analgesia must be adminis-
`Consult 1999 PDR® supplements and future editions for revisions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`|
`
`
`
`
`
`
`
`
`!
`
`
`
`
`
`
`i
`
`
`
`
`1
`
`
`
`
`
`
`

`

`
`
`938/DUPONT PHARMA
`PHYSICIANS’ DESK REFERENCE@
`
`DRUG ABUSE AND DEPENDENCE:
`ReVia—Cont.
`7
`drawal. These may include, but are not limited to; ng
`
`vomiting, dysp