`
`PHVSlClANS’
`DESK
`REFERENCE
`
`
`
`
`
`Supplement A
`
`For important errata, turn the page.
`
`IMPORTANT NOTICE
`’
`v
`-. Supplements to PHYSICIANS' DESK REFERENCE are published twice yearly to provide readers with significant revisions of existing product listings as well as
`comprehensive information on new drugs and other products not included in the current annual edition. Before prescribing or administering any product
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`to press.
`
`Cowman 0 2000 and published by Medical Economics company-a1 Monivale. NJ 076451142. all rights reserved. None or the content oi this publication may be
`reproduced. stored In a retrieval system. resoid. redistributed. or transmitted in any form or by any means (electronic. mechanical. photocopying. recording. or otherwise}
`Without the prior written permission oi the publisher. PHYSICiANS' DESK REFERENCES, 90%. PDR For Ophthalmologyiib. Pocket Penn. and The PDR® Family Gu'lde Io
`Prescription Drugem are registered trademarks used herein under license. FDR for Nonpreacnmion Drugs and Dietary Supplements”. PDRGD Medical Dictionary”. Pm
`Nurse's Drug Handbook“. Fons Nurse's Dimionary‘“. FDR Companion Guide”. PDR® for Herbal Medicines“. PDRiD'NIas 0! Anatomy. 111a PDFm Family Guide to
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`03'3"“. The PDR® Family Guide to Over-theCQuntai Drugs“ and The Pom; Family Guide to Natural Medicines endHealing ‘i'i1erapir-.-sIM are Irademarirs used herein
`under license.
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`ENDO - Ex. 2046
`
`Amneal v. Endo
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`|PR2014-00360
`
`ENDO - Ex. 2046
`Amneal v. Endo
`IPR2014-00360
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`

`

`A248IORTHO-MC__NEIL
`
`PDR supplement,lA12000
` Topamax—Cont.
`
`HOW TO TAKE
`TOPfiMAXQ [Eplrsmats “finial SFHINKLE CAPSULES
`A Guide for Patients and Their Caregivers
`Your doctor has given. you a pracription for TOPAMAX®
`(toplramate capsules) Sprinkle Capsules. Here Ire your in-
`structions for takmg this medication. Please read these in-
`structions prior to use.
`To Take With Food
`You may sprinkle the
`contents of TOPAMAX®
`Sprinkle Capsules on a
`small amount (teaspoon)
`of soft
`food, such as
`applesauce, custard, ice
`cream, oatmeal, pud-
`ding, or yogurt.
`
`Hold the capsule up-
`right so that you can
`read the word "TOP”.
`
`{ll-
`
`
`
`bamazepine during adjunctive therapy with TOPAMAX®
`may require adjustment of the dose of TOPAMAX®. Be-
`cause of the bitter taste, tablets should not be broken.
`TOPAMAX®CHII Millikan Without regard to meals.
`_
`Adults {1? Years of Age and Owl
`The recommended total daily dose of TOPAMAX® as ad-
`junctlve therapy is 400 mgfdey in two divided doses. In
`studies of adults with partial onset seizures, 1: daily dose of
`200 mglday has inconsistent ell‘scla and is less effective than
`400 Insidey. Ills-recommended that therapyhe initiated at
`fill Inglday folloWed by titration to an efl'cctive dose. Daily
`doses'abovs 1,600 mg have not been studied.
`The recommended titration rate for topir'amste is:
`AM DOSE
`PM DOSE
`none
`50 mg
`Week 1
`so mg
`no mg
`Week 2
`50 mg
`ml] rug
`Week 3
`100 mg
`100 mg
`Week '4
`100 m
`”150 mg
`Week 5
`150 mg
`150 mg
`Week 6
`150 mg
`200 mg
`Week 1'
`son mg
`Week 8
`200 mg
`In the study of primary generalized tonic-clonic seizures the
`initial titration rate was slower than in previous studies;
`the assigned dues-was reached at the end of 8 weeks (see
`CLINICAL STUDIES, Controlled Trials in Patients With
`Primary Generalized Tonic-Clonic Seizures).
`Pediatric Patients Ages 2—16 Years
`The recommended tote] daily dose of 'I‘OI’AMAXG’ (hopin-
`mnte) as sdjunctive therapy is approximahly 5'to"9 my
`day in two divided doom. 'l‘itration'should begin at 25 mg (or
`less, based .011 a' range of 1 to 3 mg/kgi’dsy) nightly for the
`first week. The dosageshould then be increased at _1- or
`2-week interyals bylhcrementa 'an to 3' mgflrgfdny (admin«
`istered in twodivided doses)._to achieve optimal clinical re-
`sponse. Dose titration should be guided by clinical'oulcome.
`In the study of-primary generalised lonic-cionio seizures the
`initial titration rate Was slower than in firevious studies;
`the assigned dues 0115 was; was real: ed at the end of
`B weeks‘lsee'GmCA'L STUDIES, Controlled'l'riats In Ps-
`tionts With Primary Generalized Tonto-Glenlosslzuresl.
`Administration or TOPAMAXO'Sprlnlfio cannula
`TOPAMAX® (topiramate capsules) Sprinkle Capsules may
`he'swall'owe'd whole or may be administered by carofirlly
`opening the capsule and sprinkling the entire contents on o_
`smali'arnount (teaspoon) ofsoft l'oodi This drugll'ood mixture
`should be swallowed immediately aod'not chewed. It should
`not be stored for future use.
`'
`'
`'
`Patients with Renal Impairment:
`In renally impaired subjects (creatinine clearance less than
`70 mL/min/L73m2), one half of the usual adult dose is rec-
`ommended. Such patients will require a longer time to reach
`steady-state at each dose.
`Patients Undergoing Hsmodlslynls:
`'Ibp'irnmate is cleared by hemodinlysis stja rate that is 4 to
`6 times greater than a annual individual. Accordingly. a pro:
`longed period of dialysis may cause topirnmste ooneentre»
`tion to fell below that required to maintain an anti-seizure
`efl'c'cL To avoid rapid drops in topiramote plasma concentra-
`tion during hemodisjysis. a supplemental dose of topira-
`rnste my be required. The actual adjusts-sent should take
`into account 1) the duration ol’dielysis period, 2) the clear—
`once rate of the dialysis system being used. and 3) the efliec-
`tivo renal clearance of topiramate in the patient being dia-
`lyzed.
`Patients with Hepatic Disease:
`In hepaticully impaired patients topiramate plasma concen-
`trations may be increased. The mechanism is not well un-
`dorstood.
`HOW SUPPLIED
`
`Carefully twist off the
`clear portion of the cap-
`sule. You may find it
`best to do this over the
`small portion of the food
`onto which you will he
`pouring the sprinkles.
`
`Sprinkle all of the cap-
`sule’s contents onto a
`spoonful of soft
`food,
`taking care to see that
`the entire prescribed
`dosage is sprinkled onto
`the food.-
`
`sure the patient
`Be
`swallows
`the
`entire
`spoonful of the sprinkle!
`food mixture immedi-
`ately. Chewing should
`be avoided. It may be
`helpful to have the pa—
`tient drink fluids imme-
`diately in order to make
`sure all of the mixture is
`swallowed.
`IMPOR—
`TANT: Never store any
`sprinkle/food mixture
`for use at a later time.
`
`643-10445-2
`
`13‘
`
`
`
`
`
`To Take Without Food
`TOPAMAX® Sprinkle Capsules may also be swallowed as
`whole capsules.
`For more information about TOPAMAX® Sprinkle Cap-
`sules, ask your doctor or pharmacist.
`0MP DIVISION
`ORTHO-McNEIL PHARMACEUTICAL, INC.
`Raritan, NJ 08869
`© 0MP 1998
`Revised October 1999
`
`
`TOPAMAX® ltopiramutc) Tablets is available as debossed,
`coated. round tablets in the following strengths and colors:
`25 mg white (coded “TOP” on one side: '25” on the other)
`100 mgyellow (coded ”TOPAMAX" on one side; “100” on the
`other)
`.
`200 mg salmon (coded "POPAMAX’ on one elde; “200” on the
`other)
`They are supplied as follows:
`25 mg tablets—bottles of60 count with desiccant (NDC 0045- ULTRAM®
`0639—65)
`(tramadol hydrochloride tablets)
`100 mg tablets—bottles of 60 count with desiccant (NDC
`0045-0641455)
`'
`,
`'
`200 mg tablets—bottles of 60 count with desiccant (NDC
`0045-0642455)
`TOPAMAX® (topiramate capsules) Sprinkle Capsules con-
`tain small, white to ofl‘ white spheres. The gelatin capsules
`are white and clear.
`They are marked as follows:
`15 mg capstds with 'TOP' and ”15 mg" on the side
`25 mg capsule with ”TOP" and “9.5 mg" on the side
`The capsules are supplied as follows:
`15 mg capsules-bottles of SD lNDC flDdh-Dfidlvfifil
`25 mgcapsules~bottles of ED (NDC ONE-064565)
`TOI’MMXID ftopiremotel Tablets should be stored in tight-
`ly-olosed containers or. controlled room temperature, {59 to
`86°F. 15 In 30°C). Protect from moisture.
`TOPAMAX® {topirsmntc capsules) Sprinkle Capsules
`should be stored in tightly‘cloeod containers at or below
`25"0 (TWP). Protect from moisture.
`TOPAMAX® ltopiramate) and TOPAMAX® (topiramate
`capsules) are trademarks of Ortho-McNeil Pharmaceutical.
`
`Prescribing infornmtion for this product, which appears on
`sugar 2218~2220 of the 2000 FDR, has been completely re-
`vised on fiillows. Please write ‘Soe Supplement A” next to the
`product flooding.
`Prescribing Information
`DESCRIPTION
`
`ULTRAM” ltramadol hydrochloride tablets} in a centrally
`acting analgesic. The chemical name for tramedol hydro‘
`chloride is [tleis-2-lldimethylaminolmothyll-l-{ii-mcth ox-
`yphenyl) cyclohexonol hydrochloride. its structural lbrmula
`15
`[See chemical structure at top of next column]
`The molecular weight of tramodol hydrochloride is 299.8.
`'l‘romedol hydrochloride is a white. hitter. crystalline and
`odorless powder. It is readily soluble in water and ethanol
`and has a pile of 9:41. The waterln-octanol partition cool’fi-
`dent is 1.35 at pH 7. ULTRAM tablets contain 50 mg oftre—
`medal hydrochloride and are white in color. Inactive ingre-
`dients in the tablet are corn starch, hydroxyprnpyl methyl-
`
`05":
`
`IHCI m I
`
`H He—N
`
`coo
`
`
`
`cellulose, lactose, magnesium stearate, microcryatalline
`cellulose, polyethylene glycol, polysorhate 80, sodium Starch
`glycolate, titanium dioxide and wax.
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`ULTRAM is a centrally acting synthetic analgesic 00m-
`pound. Although its mode of action is not completelyunday.
`stood, from animal
`tests. at least two complementary
`mechanisms appear applicable: binding of parent and .MJ
`metabolite to propioid receptors and wool: inhibition of re.
`uptake of norapinephrine and Serotonin. Opioid activity is
`due to both low afiinity binding ofthe parent compound and
`higher affinity binding of the 0-deni'ethylated metabolite
`M1 to p-opioid receptors. In animal models. M1 loop to 3
`times more potent than tramadol 'aniroducingionalge'sia
`and 200 times more potent in p-opioi binding. Wol—
`ioduced analgesia is only partially antagonized by the opiJ
`ete antagonist noloutone in several animal .tests."1'he rela~
`live contribution of both tramadol and MI. to human anal-
`gesio is dependent upon the plasma concentrations ofeaeh
`compound (see CLINICAL PHARMACOLOGY, Pharmacoki~
`notice).
`..
`Tramsdol has been shown to inhibit reuptakeof col-epi-
`nophrino and serotonin in uilm. as have some other opioid
`[analgesics Those mechanism may. contribute indepen-
`dently to the overall analgesic profile of.ULTRAM finslge
`sis in humans begins approximately within onshourul'tor
`administration and reaches-a peak in approximately two to
`three hours.
`
`Apart Erom analgesia. UL'I'RAM administration may pro-
`duce a constellation ofsympmms (including dizziness, som-
`nolenoe. nausea. mustipation, sweating and pros-ibis] simi-
`lar to that of an opioid. However, unmade! causes less tes-
`piratnry depression than morphine at reubmmeudedfiosea
`(see OVERDOSAGE). In contrast to morphine, tramadol
`has not been shown to eeunehiatamine release. At therapeu-
`tic doscs, ULTRAM has no effect on heart rate, left-ventric-
`ular Emotion or cardiac index. Urthostelic hypbtenaion has
`been observed.
`Pharmaookinetifi
`.
`The analgesic activity of ULTRAM is due to both parent
`drug and the M1 metabolite (see CLINICAL PHARMACOL—
`OGY, Pharmacodynamics). Tramadol is administered as a
`racemate and both the [—1 and [+] forms of both tramadol
`and M1 are detected in the circulation. Tramadol is well ab-
`sorbed orally with an absolute hioavailability of 1.5%. Tra-
`madol has 'a volume of distribution ofapproxirnstely'dflls’kg
`and is only son bouodto plasma proteins. Tramsdol is a:-
`teosively metabolized by a number-of pathways, including
`CYP2D3 and CYP3A4. as well as by conjugation of parent
`and metabolites. One metabolite. M1. is phermacologiailly
`active in animal models; The {emotion of M1 is'dependont
`upon Cytochrome P450l2D3) and as such is subject to-both
`metabolic induction and inhibition which may client the
`therapeutic response (see PRECAUTIONS—Drug Interac-
`tions}. “unmade-l and its metabolites are exacted primarily
`in the urine with observed plasma half-lives of 5.3 and 'lA
`hours for tramadol and M1, respectively. Linear pharmaco-
`kinetics hevebeen observed following multiple doses of 60
`and 100 mg to steady-state.
`Absorption:
`Racernic tramadol is rapidly and almost completely ab-
`sorbed afier oral administration. The mean absolute bio-
`availability of a 100 mg oral dose is approximately 7.5%..Thc
`mean peak plasma ooncontrsfion of racemic tramadol and
`M1 occurs at two and three hours. respectively..sher admin-
`istration in healthy'adulls. In general, both enmtiomera of
`tremadol and M1 follow a parallel time course in the body
`following single and multiple doses although small diderv
`sores (“41096) exist in the absolute mount of each enactin-
`mer present.
`Steadystate plasma concentrations of both tramadol and
`M1 are achieved within two days with q.i.d. dosing. There is
`no evidence of self-induction (see Figure 1 and Table 1 be-
`low).
`[See figure 1 at top of next page}
`[See table I at bottom of next pagel
`Food Efi’ectsr Oral administration of ULTRAM with food
`does not significantly affect its rate or extent of absorption,
`therefore, ULTRAM can be administered without regard to
`food.
`Distribution.-
`The volume of distribution of tramadol was 2.6 and 2.9 1i—
`teral‘lsg in male and female subjects. respectively, lollowing s
`100 mg intravenous dose. The binding oi‘trsmadol to human
`plasma proteins is approximately 20% end binding also ap-
`pears to be independent of concentration up a: ll] uglmL.
`Saturation ol'ploamn protein binding occurs only at ounoon-
`trulions outside the clinically relevant range. Although not
`confirmed in humans, trsmadol has been shown in rats to
`cross the blood-brain barrier.
`Metabolism:
`Tramadol is extensively metabolized afier oral administra-
`tion. Approximately 30% of the dose is excreted in the urine
`as unchanged drug, whereas 60% of the dose is excreted as
`
`

`

`
`
`--l-— llamadfl
`(mum
`—-—— 11m
`snore-so
`
`
`m
`
`no
`
`
`“'0
`
`
`lw
`names-o
`
`----- in)
`
`W“!
`
`
`0
`
`I!
`
`24
`1am an
`
`ill
`
`metaboliws. The remainder is excreted either as unidenti-
`fiedor aszaunextrsdshle metabolites. The major metabolic
`pathways appear to be N- and O-demethylation and lucu~
`mnidation or'.'sulfation' in the liver. Oneimatsbolitel
`ea-
`mcthyltrsmadol. denoted M1] is pherms'celopicslly active in
`animal models. Production of M1 is dependent on the
`SCYPZDE ieosezyme ol‘_
`roe 13—450 and as such is sub-
`ject-to both metabolic-induction and inhibition which may
`afoot the therapeutic response (see PREGAUTIONEDmg
`Interaction).
`Approximately 7% of the population has reduced activity of
`the CW6 tenancy-me of cyooclwome-P—Ilfiu. Those indi»
`viduals are ‘poor metaboliscre' of debrisoqifine. dextro-
`methorpbao. tricyclic antidepressants, among other drugs.
`Afici- s single oral dose oil's-smsdol. concentrations oftra-
`madol were only slightly higher in ‘poor metabolism-8' ver-
`sus “extensive minsboliam-e". '
`'
`‘
`
`Gmnfi'sueh'aa fluesetine and its metabolite norfluo'creh‘ne.
`emitriptyline and quinidine inhibit the metabolism of-i:rn«
`model to various dayees.'suggesting'that.90mniitant ad'
`ministration ofthsee compounds omild result in increases'in
`trainsdol' concentrations and. decreased concentrations of
`M1. The phaidnaoologicsl impact of these alterations in
`terms of either eficacy .or safety is unknown.
`
`
`
`
`
`
`
`
`8PMDlsoonllnulng E
`
`
`15
`‘0
`DayllnDoufle-Bhnd
`
`un I nU'IVIVIILII.’ rib-r9
`
`PDR Supplement A/2000
`‘ Tricyclic antidepressants (TCAsl. and other tricyclic com-
`ULTRAM has been studied in three loopterm controlled tri-
`pounds le.g., cyclobenzaprine, promethazine, etc), or
`Moon 'l‘rmnadol and M1 Plasma {lonocnlmtion
`figure 1:
`als involving a total of 820 patients. with 530 patients re-_
`' Opioids.
`Profiles after a Single mo mg Ore] Dose and af-
`oeiving ULT'RAM. Patients with o variety of chronic painful
`Administration of ULTRAM may enhance the seizure risk in
`ter 'Dzventy—Nine 100 mg Oral Doses ofTromadol
`conditions were studied in double-blind trials of one to three
`patients taking:
`H01 given q.i.d.
`WARNINGS—Use with MAO In-
`months duration. Average dolly doses of approximately 250
`' MAO inhibitors (see also
`hibitorsl.
`mg ofUL'I'RAM in divided doses were generally comparable
`to five doses of acetaminophen 30E} rogwith codeine phos-
`0 Naurnleptlcs. or
`phate 30 mg (MENDL‘ with Codeine #3) daily, llvo doses
`0 Other drugs that reduce the seizure threshold.
`of aspirin 325 mg with codeine phosphate 30 mg daily. or
`Risk oi convulsions may also increase in patients with en-
`two to three doses of acetaminophen 590 mg with oxycodone
`llepsy. those with a hlstory of seizures. or in patients with a
`hydrochloride ii mg lTYLOX‘”) daily.
`recognized risk tor seizure lsuch as head trauma. metabolic
`Tilratlon Trials
`disorders. alcohol and drug withdrawal. CNS infections}. In
`in a randomized. blinded clinical study with 129 to 132 pa-
`ULTRAM overdose, naloxone administration may increase
`the risk of seizure.
`tients per group. a 10-day titration to a dolly ULTRAM dose
`of 200 mg (50 mg q.i.d.J. attained in 50 mg increments aver-y
`Ansphylactold Reactions
`3 days. was found to result in fewer discontinuation due to
`Serious and rarely fatal snaphyloetnid reactions haw: been
`dissineso or vertigo than titration over only 4 days or en ti-
`reported in patients receiving therapy with UIJI‘RAM.
`tration. lo a second study with 54 to 59 patients per group.
`These reactions often occur following the first. dose. Other
`patients who had nausea or vomiting when titrated over 4
`reported reactions include pruritus. hives. bronchospasm.
`days were randomised to re-initiate ULTRAM therapy using
`and angioedemn. Patients with a history of anephyluctoid
`slower titration rates. A 16-day titration schedule. starting
`reactions to codeine and other opinids may be at increased
`with 25 mg qAM and using additions] doses in 25 mg incre-
`risk and therefore should not receive ULTRAM (see CON-
`ments every third day to 100 mp’dsy (25 rag q.i.d.}. followed
`TRAINDICATIONS).
`by 50 mg increments in the total daily dose every third day
`Use In Opioid-dependant Patlanur
`to 201} mafday (50 mg q.i.d.l. resulted in fewer discontinue-
`ULTRAM ”should not be used in opioiddependont patients.
`tines due to nausea
`or vomiting and footer disconfinuefions
`ULTRAM has been shown to reinitiate physical dependence
`did a 10-day titration schedule.
`due to any cause than
`in some patients that have been previously dependent on
`other opioids. Cooaeq _
`tip, in patients laid: a tondoncy to
`opioid abuse or opioid dependence.
`treatment with
`ULTRAM is not recommended.
`Uaowi'th CNS Depressants
`ULTRAM should be used with caution and in reduced dos-
`ages when administered to
`tionle' receiving-CNS depres-
`seats such as alcohol. opioi
`. anesthetic agents; phoned-ii-
`asides. tranquilizers or sedative hypnotics.
`Use with MAO Inhibitors
`Use; ULTRAM with great caution in ps'tienhi'toking mono-
`amiue oxidase inhibitors, Because animal studies have
`shown increased deaths with combined administration.
`PRECAUTIONS
`
`Respiratory Bopresslon
`
`with anesthetic medications err-alcohol. respira-
`tory depression may result 'li'eat such cases as so
`.
`Ifnalonooe is to he administered. use cautiously because it
`may precipitate ssisures (seeWARNWGS. Seizure Risk and
`OVERDOSAGE).
`Increased Ina-scrapie! Pressure or Head Trauma
`ULTRAM should he used with caution in patients with ire
`creased intracranial pressure 'or head injury. Papillary
`changes (mioais) from trsrnudol may obscure die existence.
`extent, or course ofintrecr'anial pstlmlogy. Clirdcians should
`also maintains high index of suspicion for sdversedrug re-
`action when evaluating altered mental status in these pa-
`tients if they are reeeising norm.
`Acute Abdominal Conditions
`The administration ofULTRAM may complicate the clinical
`assessment of patients with acute abdominal conditions.
`Withdrawal
`'
`Withdrawal symptoms may occur if ULTRAMj’ (trumadol
`hydrochloride tablets} is discontinued abruptly These symp-
`toms may includsr'anidety. sweating. insomnia. rigors. pain.
`nausea. homers, diarrhoea. upper respiratory symptoms.
`Continued on next page
`
`'I‘lie'mean terminal plasma elimination half-lives oft-anemic
`madolandraoemich are 3.3 1 1.4 and’i'A : 1.4 hours.
`respeeiiVely The plasma elimination hallilifeofraoemic tra»
`medal increased from approximately six hours to seven
`hours upon multiple dosing.
`Special l’opulnlona
`Renal:
`_
`lmpsirsdrenal function results in a decreased rate and en-
`tont of emotion of unmade] and its active metabolite. M1.
`In
`fiesta with crestinins clearances of less than 30
`Int-gm.adiusenvnt oftha deems regimen ismmmmandeci
`(soeDQSAGE ANDADWISTRATION). The total amount
`oftramsdol and M1 removed during a 4-hour dialysis period
`is lengthen 7% of the-administered dose.
`ego
`.
`Metabolism ofh‘amadol and Mlis reduced in patients with
`sdsanoed cirrhosis of the liver. resulting in both a larger
`area under the concentration time curve for trainsan and
`lingers-emetic) and M1 elimination half-lives (13 lira. for
`Table 1
`trnmhdnl and 19 hrs. for M1). In eii'rhotic patients. adjust-
`maul; ofths dosh): regimen is recommended (nee DOSAGE
`Mean (“/oCV) Pharmaeokinetic Parameters for
`AND ADMINISTRATION).
`'
`Racemic Tramadol and M1 Metabolite
`Ass:
`.
`
`
`Healthy elderly subjects aged 65 to 15 years have plasma
`tm (hrs)
`Population]
`Clearance/Fb
`Parent Drug/
`trsmadol concentrations and. elimination half-lives comps-
`
`Dosage Regimen“
`Metabolite
`(mllmin/Kg)
`
`rsble to those observed in healthy subjects less than 65
`
`
`years of age. In so '
`ts over ‘15 years. mexhnum oer-Inn
`592 (30)
`2.3 (61)
`5.90 (25)
`Healthy Adults,
`Tramadol
`6.7 (15)
`
`
`wooenusfiona are a glitly elevated (203 vs. 182 nyml.) and
`100 mg qid.
`110 (29)
`2.4 (46) — 7.0 (14)
`MD p.o.
`M1
`the-elimination h'slf-life‘ls‘slightly prolonBEd (7 vs. 6 hours)
`._
`\to sohjeots 651.0 ’15 years ofnge. Adjustment of
`
`the daily dose is recommended for patients older than 75
`Healthy Adults.
`1— Tramadol
`308 (25)
`1.6 (63)
`8.50 (31)
`5.6 (20)
`
`steers (see DOSAGE AND nDIflNIS'I'RATIONJ.
`100 mg
`SD p.o.
`M1
`55.0 (36)
`3.0 (51)
`c
`6.7 (16)
`
`The absolute bioevailability of tramsdol was 1'39!» inmales
`Tramadol
`208 (31)
`2.1 (19)
`6.89 (25)
`7.0 (23)
`Geriatric,
`and 19%;
`in females: The plasma clearance was 3.4
`
`mIJminikg in males and 5.7 mIJniinfkg infem‘slee following
`(>75 yrs)
`50 mg SD p.o.
`M1
`(1
`d
`c
`d
`all!!! mg N done of iramadol. Following a oingl'e oral dose.
`ond'after sdiusting for body weight. females had n 12%
`
`Hepatic Impaired,
`Tramadol
`217 (11)
`1.9 (16)
`4.23 (56)
`13.3 (11)
`higher peak tramadol concentration and s 35% higher area
`under theooncootrstion-time curve oompered to males. The
`50 mg
`SD p.o.
`MI
`19.4 (12)
`9.8 (20)
`c
`18.5 (15)
`clinical significance of'this difi‘ere'oco is urilmo'im.
`Clinical Studies
`
`Renal Impaired.
`’l‘ramadol — ' c
`4.23 (54)
`10.6 (31)
`ULTRAM has been given in single oral doses of 50.25. 100.
`150 and son mg to patients with pmn_fohowin£_$urgiosl pru-
`CLcr 10-30 mIJmin
`100 mg SD i.v.
`M1
`0
`c
`c
`11.5 (40)
`cedoros and pain following oral surgery (extraction of im-
`
`pacted molars}.
`_
`_
`.
`_
`Renal Impaired,
`Tramadol
`c
`c
`3.73 (17)
`11.0 (29)
`1n single-dose models of pain'foilowing oral surgery. pain ro-
`h‘cf was demonstrated in some patients at dosesol' fill mg
`CLC,<5 mL/Inin
`J___
`100 mg SD i.v.
`M1
`0
`c
`c
`16.9 (18)
`of 100 mg ULTRAM tended to provide
`
`analgesia superior to-oodeine sulfate 60 mg. but it was not
`MD = Multiple dose. p.o. = Dru] administration.
`3 SD 2: Single dose.
`deinephosphsta 60 mg In amgledosc models ofpain follow-
`i.v. = Intravenous administration. qid s Four times daily
`mg surgical
`. um. 150 mg provided analgesia geocr:
`b i" represents the oral bioavailsbility of tramsdol
`allycompara
`to the mbina'tion of '
`'eophsm .650
`
`series 100 ms. with a tendency c Not'spplic'ahle
`d Not measured
`
`
`
`
`INDICATIONS AND USAGE
`ULTRAM is indicated for the management of moderate to
`moderately severe pain.
`cow'raammcas'losa
`ULTRAM should not beadministered to patients who have
`previously demonstrated hypersensitivity to tramadol. any
`other component of this product or opioids. It'is also contra-
`indicated in cases of‘acute intoxication with alcohol. hypnot-
`:1).chlll centrally acting analgesics. opioida or psychotropic
`gs.
`WARNINGS
`
`Seizures have been reported in patients receiving ULTMM
`within the recommended dosage range. Spontaneous
`post-merketlng reports Indicate that seizure rial: Is In-
`creased with doses of ULTRA”! shove the recommended
`range. Concomitant use of ULTHAM influence the seizure
`risk in patients taking:
`0 Sole'cfiua motorfin "uptake inhibitors (SSRI antidepres-
`sants or anorectiosl,
`
`
`
`

`

`ALOUIUH l HU-MUNEIL
`
`Ultram—Cont.
`
`Use with Digoxin and Warforin
`Post-marketing surveillance has revealed rare reports of di!
`goxin toxicity'and alteration of warfarin elfect, including el-
`piloerection, and rarely hallucinations. Clinical experience
`evation of protllrombin times.
`suggests that withdrawal symptoms may be relieved by ta-
`Carcinogenesis, Mutagenesis. lln airmen: of Fartillty
`pering the medication.
`Tramadol was not mutagenic in‘
`e followin assays: Ames
`Patients Physically Dependent on Opioids
`Salmonella microsomal activation toot, CH HPET mam-
`ULTRAM is not recommended for patients who are depen-
`malian cell assay, mouse lymphoma assay (in the absence of
`dent on opioids. Patients who have recently taken substan-
`metabolic activation), dominant lethal mutation tests in
`mice, chromosome aberration test in Chinese hamsters, and
`tial amounts 0f opioids may experience withdrawal symp-
`bone marrow microuucleus tests in mice and Chinese ham-
`toms. Because-of the dilficulty in assessing dependence in
`patients-who have previously received substantial amounts
`sters. Weakly mutagenic results occurred in the presence of
`of opioid medication, administer ULTRAM cautiously to
`metabolic activation in the mouse lymphoma assay and mi-
`such patients.
`cronuclaua test in rats. Overall, the weight of evidence from
`Use in Renal and Hepatic Disease
`these tests indicates that tramadol does 'not pose a genotoxic
`risk to humans.
`Impaired renal function results in a decreased rate and ex-
`tent of excretion of tramadol and its active metabolite, M1.
`A slight, but statistically significant, increase in two com-
`In patients with creatinine clearances of less than 30
`mon murine tumors, pulmonary and hepatic, was observed
`mIJmin, dosing reduction is recommended (see DOSAGE
`in a mouse carcinogenicity study, particularly in aged mice
`AND ADMINISTRATION).
`(dosing orally up to 30 mg/kg for approximately two years,
`although the study was not done with the Maximum ’lhler-
`Metabolism of tramadol and M1 is reduced in patients with
`ated Dose). This finding is not believed to suggest risk in
`advanced cirrhosis of the liver. In-drrhoIic-pafianta. dosing
`reduction is recommended (see DOSAGE AND ADMINIS.
`humans. No such finding occurred in a rat carcinogenicity
`TRATION).
`study.
`With the prolonged half-life in these conditions, achieve-
`No effects on fertility were observed for tramadol at oral
`ment of steady-state is delayed, so that it may take several
`dose levels up to 50 mg/kg in male rats and 75 mg/kg in
`female rats.
`days for elevated plasma concentrations to develop.
`Information for Patients
`Pregnancy, Thratogenic Efi'ects: Playmate)! Category C
`0 ULTRAM may impairmental or physical abilities required There
`are lie-adequatean'd well-controlled studies in preg‘
`for the performance of potentially hazardous tasks such as
`nent women.‘ ULTRAM should be used during pregnancy
`driving a car or operating machinery.
`only if the potsntial'beneiltjuatifies the potential risk to the
`fetus.
`0 ULTRAM should not be taken with alcohol containing
`beverages.
`’I‘ramadol has been shown to be embryotoxic and fetotoxic in
`mice, rats and rabbits at maternally toxic doses 3 to 15
`' ULTRAM should he used with caution when taking medi-
`cations such as tranquilizers, hypnotics or other opiate
`times the maximum human dose or higher (120 mg/kg in
`containing analgesics.
`_
`mice. 25
`or bighar in rats and 75 mg/kg or higher in
`0 The patient should be instruclcd to inform the physician if
`rabbits); but was not torstogenic at these dose levels. No
`harm to the fetus due to tramadol was seen at doses that
`they are pregnant, think they might becomcpregrmnt, or
`are trying to become pregnant (see PRECAUTIONS: La-
`were not maternally toxic.
`bor and Delivery).
`No drug—related teratogenic effects were observed in prog—
`0 The patient should understand the single-dose and 24-
`eny of mice, rats or rabbits treated with tramadol by various
`hour dose limit and the time interval between doses, since
`routes (up to 140 mg/kg for mice, 80 mg/kg for rats or 300
`exceeding these recommendations can result in respira-
`mg/kg for rabbits). Embryo and fetal toxicity consisted pri-
`tory depression and seizures.
`marily of decreased fetal weights, skeletal ossification and
`Drug Interactions
`increased-supernumorory ribs at maternally toxic dose lev-
`Tramadol does not appear to induce its own metabolism in
`els. 'l‘ron'sient delays in developmental or behavioral param-
`humans, since observed maximal plasma concentrations af-
`eters were also seen in pups froinrst dams allowed to de-
`ter. multiple oral dosesaro higher than expected based on
`liver. Embryo and fetal lethality were reported only in one
`rabbit study at 300 mg/kg, a dose that would cause extreme
`single-dose data. 'ltamodol is amild inducer of selected drug
`metabolism pathways measured in animals.
`maternal toxicity in the rabbit.
`Use with Carbamazepine
`In peri- and post—natal studies in rats, progeny of dams re-
`Concomitant administration of ULTRAM with carbamaze-
`ceiving oral (garage) dose levels of'bl) mgfkg or'graatcr had
`pine causes a significant increase in tramadol metabolism,
`decreased weights, and pup survival was decreased early in
`lactation at 80 mgfkg (6' to 10 times the maximum human
`presumably Lluough metabolic induction by corbamonapine.
`Patients receiving chronic mrbamaeepino doses of up to 800
`dose). No toxicity was observed for progeny of dams receiv—
`mg daily may require up to twice the recommended dose of
`ing 8, 1t}, 20, 25 or 40 Ingfirg. Maternal toxicity was observed
`ULTRAM.
`at all dose levels, but «floats on progeny were evident only at
`Use with Quinidine
`higher dose levels where maternal toxicity was more severe.
`Labor and Delivery
`'I‘ramadol is metabolized to M1 by the CYP2D6 P-450 isoen-
`zyme. Ouinidine is a selective inhibitor of that isoenzyme, so
`ULTRAM should not be used in pregnant women prior to or
`that concomitant administration of quinidine and ULTRAM
`during labor unless the potential benefits outweigh the
`results in increased concentrations of tramadol and reduced
`risks. Safe use in pregnancy has not been established.
`concentrations of M1. The clinical consequences of these find-
`Chronic useduring pregnancy may lead to physical depen-
`ings are unknown. In vitro drug interaction studies in hu-
`dence and postpartlm: W'ifltdl‘aWal symptoms in the new-
`man liver microsomes indicate that tramadol has no efl'ect on
`born. 'I'ram‘adol has been shown to cross the placenta. The
`quinidine metabolism.
`mean ratio of serum tramadol in the umbilical veins com-
`Use with Inhibitors of CYP2D6
`pared to maternal veins was 0.83 for 40 women given tra-
`In vitro drug interaction studies in human liver microsomes
`madol during labor.
`indicate that concomitant administration with inhibitors of
`The effect of ULTRAM, if any, on the later growth, develop-
`ment, and functional maturation of the child is unknown.
`CYP2D6 such as fluoxetine, paroxetine, and amitriptyline
`could result in some inhibition of the metabolism of trama-
`Nursing Mothers
`dol.
`UL