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`...••.....••....
`
`APOTEX_AZFL 0061704
`
`DTX-048.0001
`
`1
`
`CIP2043
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`r
`
`AUSTRALIA'S JOURNAL OF PRACTICAL DRUG TREATMENT
`
`.,
`
`.... , .. Contents
`
`December 1986•Vol. 27 No. 12 JSSN 0311-905X
`
`GUEST EDITORIAL
`
`Fixed Drug Combinations
`Which Ones Can be Recommended?
`The view of drug regulatory bodies in Australasia is that fixed combination preparations
`are rarely necessary; sales figures, however, suggest they are extremely popular with
`patients and doctors ali ke. Only a limited number have been available until now but the
`scene is set for the possible introduction of many more. Doctors, therefore, should be
`aware of the potential advantages and disadvantages
`
`G.M. Shenfield (Sydney)
`
`15
`
`P A G E
`
`PRACTICAL THERAPEUTICS
`
`Drugs and Alcohol
`Their Interactions and How to A void Them
`Because alcohol is consumed on such a grand scale, in numeri cal terms, interactions
`between drugs and alcohol are important This article discusses interactions that are
`particularly hazardous, especially those involving drugs in everyday use, and gives
`practical recommendations on how to avoid them
`
`J.B. Saunders (Camperdown, NSW)
`
`31
`
`P A G E
`
`CURRENT TH ERAPEU TI CS DECEMBER 1986
`
`CO NT EN T S C ONTINU ED O N PA GE 4
`
`This material w as copie-d
`at t he NLM and may be·
`Su bj ec:t US ·Copyright Law s
`
`APOTEX AZFL 0061705
`
`DTX-048.0002
`
`2
`
`

`

`PRACTICAL THERAPEUTICS continued
`Therapeutic Uses of
`Vitamin B12, Iron and Folate
`Because the haematinics, iron, vitamin B12 and folate, should only be used when a
`specific deficiency exists, it is imperative that the precise deficiency is determined and the
`cause diagnosed. Once an accurate diagnosis has been made, as outlined in this article,
`definitive treatment of the cause and replacement of the deficient haematinic is
`appropriate
`
`G.N. Brodie (Melbourne)
`
`55
`Constipation in Adults
`Constipation is a frequent symptom in Western communities and a wide range of
`therapeutic agents is available to trea t it. Before prescribing laxatives, however, it is
`important that the general practitioner excludes or corrects any underlying pathology and
`pays attention to factors such as diet, exercise and development of regular bowel habits,
`as this may be all that is required
`
`PAGE
`
`P.R.H. Barnes (Sydney)
`
`PAGE
`
`69
`Infections in Bones and Joints
`Part II. Infectious Arthritis
`Septic arthritis is a relati vely common medical emergency which may result in permanent
`joint dam age unless treatment is initiated within I to 2 days. This part of the article
`discusses the microbiology and antibiotic therapy which has virtually eliminated mortality
`caused by infectious arthritis
`A.S. Dickie (Auckland)
`
`81
`
`P A G E
`
`THERAPEUTIC GUIDES
`
`Summary of Investigations of Macrocytic Anaemia p. 60
`Summary of the Management of Infectious Arthritis p. 96
`
`4
`
`CO NT ENT S CO NTINU ED ON PAGE 5
`
`Thi.s m ateria l w as •c.opied
`
`CURRENT THERAPEUTICS DECEMBER 1986
`
`APOTEX AZFL 0061706
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`DTX-048. 0003
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`

`

`urreht
`herapeutics
`
`KEYNOTES
`
`11
`
`P A GE
`
`SELECTED SUMMARIES
`
`100
`
`P AGE
`
`NEW PRODUCTS
`
`113
`
`P A G E
`
`ADVERTISERS ' INDEX
`
`113
`
`P A G E
`
`INDEX
`Index to Current Therapeutics 1984-1986
`115
`
`P A G E
`
`Erratum
`Current Therapeutics, Vol. 27, No . 11 (November 1986) : In the new product entry for Natrilix Tablets
`on page 152 it should be noted that it was incorrectly stated that asthma is a side effect of this product. This
`should have read 'Other side effects include asthenia, headache, dizziness, vertigo and muscle cramps'.
`
`PUBLISHER. Current Therapeutics is publi shed on the 8th of each momh by A DIS Press Austra lasia l'ty Limited, 404 Sydney Road, Balgowlah, 2093. Telephone Sydney
`949-2022. Please address all correspondence to Current ThcrapeUiics, P.O. Box 132. Balgowlah , NSW 2093. Phone 949-2022.
`Prin1ed and bound by Promail Prin1ing Group Pty Lid, 37-39 Whiting Street, Anarmon, NSW 2064.
`EDITORIAL. Current Therapeutics is a continuing ed ucation journal in the area of drug therapy and treatment of specific disease entities.
`CIRCU LATION. Curren t Therapeutics is a journal for medical practitioners in clinical practice and hospital chief pharmacists in AuSiralia. Current Therapeutics is available
`on subscription to members of allied professions.
`SUBSC RIPTION RATES. Ausl. Residellls (incl. P. +H). Current TherapeUiics- $60/ 1 yr : $100/2 yrs. Combined with Pa!ient Management- $ 100/1 yr : $1 80/2 yrs.
`Students - $45/ I yr : $80/2 yrs. Back op1es - $4 /s ubscnbers : $8/non subscnbcrs. Overseas - $SA90 (mel. surface mall - alftnail on request).
`EDITORIAL MATTER published h erein has been prep:1red by the professional. edi torial stall' and by honorary specialist consultants from all fi elds of medicine. Although
`great care has been w~cn Ill ~o mp 1 llng a~d c hl!~k 1 n g the 1~format10n g1vcn ~n th~ s pub llc~uon to. ensure that It IS ~cc.uratl! th.c authors,. the publ isher, their servants or agents
`shall not be responsible or II\ any way il<tblc for the contmucd cw:r~ n cy ol the mforma~10n o~ for any crr~rs. O l~llSSions or maccuractes in this publication whether arising
`from negligence or otherwise howsoeve r or for any consequences ansmg therefrom. The InclusiOn or cxcluSIOTl of any product docs not mea n that the publisher ad
`t
`rejects its usc. either generally, or in any particular field or field s.
`voca cs or
`ADVERTISEME NTS arc subject to editorial accepta nce and have no influence on editorial content or presentation.
`©Copyrigh t 1986 by ADIS Press Australasia Pty Limited.
`All rights reserved throughout the world. No pan of this journal may be reproduced by any process in any language without written consent of the publisher.
`
`CU RRENT THERAPEUTI CS DECEMBER 1986
`
`Thi.s. material w as copie-d
`at the NLM and may b.e
`Su b.j e rt US Copyright Law s
`
`5
`
`APOTEX_AZFL 0061707
`
`DTX-048.0004
`
`4
`
`

`

`GUEST EDITORIAL
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Gillian M. Shenfield
`Department of Clinical Pharmacology, Royal North Shore Hospital, St. Leonards, NSW
`
`Fixed Drug
`Combinations
`Which Ones Can Be Recommended?
`
`A combination should only be prescribed if
`each component is known to be necessary for
`the desired therapeutic effect. In addition the
`advantages of using a combination rather than
`a single drug should outweigh the added risks
`of using 2 or more drugs
`
`ost patients on long term treatment
`with therapeutic drugs usually take
`more than one item. The more indi(cid:173)
`vidual tablets that are prescribed, the
`greater the potential problems of com(cid:173)
`pliance and of lack of control of the underlying con(cid:173)
`dition. Intuitively it seems obvious that it would be
`more difl'icult to remember to take 2 tablets than to
`take l, or to take l 0 than to take 5. It is therefore
`tempting to consider the use of fi xed combination
`preparations which contain 2 or more drugs in one
`formulation. This would reduce the number of doses
`to be taken and, hopefully, reduce the number missed.
`However, the situation is not that simple and there
`are clearly very different opinions held by everyone
`who considers the problem. At the extremes are the
`regulatory authorities and the pharmaceutical manu(cid:173)
`facturers. There are about 1000 fixed combination
`
`preparations listed in Mims but, excluding oral con(cid:173)
`traceptive preparations, insulins, topical agents and
`antacids, there are under 20 fixed combination tablets
`available on pharmaceutical benefits. This regulatory
`control is in keeping with the WHO list of 'essential'
`drugs which includes only 7 drug combinations; less
`than 3% of the total [ 1]. Thus, the view of drug regu(cid:173)
`latory bodies is that fixed combination preparations
`are rarely necessary. On the other hand , sales figures
`suggest that they are extremely popular with both doc(cid:173)
`tors and patients.
`
`Potential Advantages of Fixed Drug
`Combinations
`
`The potential advantages of using fi xed drug com(cid:173)
`binations are li sted in table I.
`
`CURRENT THERA PEUTICS DECEMBER I986
`
`I 5
`
`Th,is materia l w as ~:o p i E-d
`
`APOTEX AZFL 0061708
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`DTX-048.0005
`
`5
`
`

`

`... Fixed Drug Combinations
`
`Table I.
`Potential advantages of fixed drug combinations
`
`Improved compliance
`
`Synergism
`
`Enhanced efficacy
`
`Reduced side effects
`
`Increased safety
`
`Decreased potential for abuse
`
`Reduced cost
`
`Improved Compliance
`
`The most frequently quoted reason for using fixed
`combination products is improved compliance. It
`seems reasonable to assume that the greater conven(cid:173)
`ience of a single tablet would increase compliance and
`this has been observed for prophylactic iron in preg(cid:173)
`nancy [2] and for psychiatric outpatient therapy [3].
`However, in neither of these studies was there any
`observable difference in therapeutic outcome. A more
`recent study of combination tablets containing a ~­
`blocker and a thiazide diuretic found that 75% of
`patients preferred to take l tablet daily (as opposed
`to 2) but that combining 2 drugs in a single tablet had
`no effect on compliance [ 4]. Overall it appears that
`the vital factor is not the number of tablets taken but
`the number of doses prescribed.
`
`Synergism
`
`A fixed ratio drug combination can always be jus(cid:173)
`tified if its therapeutic effect exceeds the total effects
`of its components given separately in the same doses.
`The best known example of this is co-trimoxazole
`where the 2 components interfere selectively with 2
`successive steps in bacterial folate metabolism. How(cid:173)
`ever, synergy probably operates only rarely under the
`conditions in which the combination is used in vivo
`[5]. Combinations of the antimalarial pyrimethamine
`with dapsone or sulphadoxine also come into the cat(cid:173)
`egory of good synergistic combinations provided they
`are used in appropriate geographical areas. Recently
`
`a combination of amoxycillin and clavulanic acid (a
`~-lactamase inhibitor) has been introduced and this
`has a much wider spectrum of antimicrobial activity
`than amoxycillin alone. Other good examples are hard
`to find.
`
`Enhanced Efficacy
`
`In the absence of true synergy there may still be
`enhanced efficacy as illustrated by levodopa with
`peripheral decarboxylase inhibitors and combined oral
`contraceptive preparations. The use of probenecid to
`reduce renal excretion of penicillin also comes into
`this category but the combined preparation is not
`available in Australasia. A new antibiotic, imipenem,
`is very rapidly hydrolysed by a renal dehydropepti(cid:173)
`dase enzyme. This means that the drug is rendered
`inactive and it also appears to cause renal toxicity.
`The process can be blocked by cilistatin, an inhibitor
`of the renal enzyme. Cilistatin alone has no antibiotic
`activity and imipenem alone has very little antimi(cid:173)
`crobial effect, therefore they are always given in com(cid:173)
`bination to enhance the action of imipenem. Apart
`from these examples it is hard to find good clinical
`trials providing evidence for increased efficacy of
`combinations. In particular, combination analgesics
`have not been shown to be better than their individ(cid:173)
`ual components when tested in controlled trials.
`
`Reduction of Side Effects
`
`Supporters of combination therapy suggest that it
`is safer to use combinations of drugs proven to be safe
`and effective together than to indulge in indiscrimi(cid:173)
`nate polypharmacy. This would be true if all appro(cid:173)
`priate tests of therapeutic effect and pharmacokinetic
`and pharmacodynamic interactions had been per(cid:173)
`formed for all available combination drugs. Unfor(cid:173)
`tunately this is not the case and it cannot be assumed
`that all of them are automatically 'safe' [6].
`
`Decreased Potential for Abuse
`
`Occasionally addictive drugs are used for relatively
`minor purposes and an example of this is the opioid
`antidiarrhoeal agent, diphenoxylate. To discourage
`deliberate abuse and overdose it is only marketed in
`a combined preparation which contains 0.025mg of
`
`16
`
`CU RRENT T HERAPEUTICS DECEMBER 1986
`
`This. m at eri al w as copi<>d
`atthe Nl M and may be.
`
`APOTEX_AZFL 0061709
`
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`
`6
`
`

`

`60mg tablets
`Going beyond the limits of
`convention~!~Ur~~Xol!:eatment
`
`anhe· NILM and may l>e
`Sul>jen US Copyright Laws
`
`·
`
`APOTEX_AZFL 0061710
`
`DTX-048.0007
`
`7
`
`

`

`APOTEX_AZFL 0061711
`
`DTX-048.0008
`
`8
`
`

`

`ACTS ONLY ON PERIPHERAL
`H1 RECEPTORS
`AT THERAPEUTIC DOSES.
`Unlike conventional antihistamines TELDANE or its
`metabolites do not cross the blood brain b4-rrier at effective
`therapeutic doses in sufficient quantity to affect the CNS.
`Hence TELDANE acts only on peripheral H1 receptors.
`The inability of TELDANE to cr0ss the blood brain
`barrier has been confirmed by quantitative EEG.
`"Terfenadine (TELDANE) failed to elicit the characteristic
`EEG or behavioural effects of sedative antihistaminics .... "(1)
`NON-SEDATING.
`SEDATION EQUIVALENT TO PLACEBO.
`
`In double~blind, ran~
`domized, placebo~controlled
`studies involving 2,014 sub~
`jects, the reported incidence
`of sedation with TELDANE
`60 mg b. d. did not differ signi~
`ficantly from that of placebo,
`while chlorphenirainine 4 mg t. i. d. produced twice the incidence. (2
`•
`)
`5
`4
`Studies of driving performance(~land co~ordination and reaction timJ
`tonfirm
`;
`that the impairment of performance with TELDANE did not differ from placebo.
`NO POTENTIATION OF SEDATIVE EFFECTS
`OF ALCOHOL OR BENZODIAZEPINES.
`TELDANE was demonstrated to induce no potentiation of sedative effects of
`alcohol or diazepam in a comparative trial with diphenhydramine. (6
`)
`
`Sedation-free relief of allergic rhinitis.
`
`Thi.s mat erial W i3S <:o~ ied
`
`APOTEX_AZFL 0061712
`
`DTX-048.0009
`
`9
`
`

`

`EFFICACY EQUAL TO CONVENTIONAL THERAPY.
`British and American studies comparing it with other treatments have shown
`that TELDANE is as effective as chlorpheniramine in relieving the symptoms of sea,
`sonal allergic rhinitis and conjunctivitis.0·8
`COMBINED SYMPTOM SCOR
`l
`The combined symptom severity
`·
`• Terfenadinc (N = 113)
`scores of seven allergy symptoms were
`• Chlorphenuamine (N = 119)
`1 Placebo (N = 113)
`rated during the treatment period by
`II
`patients.
`sneezing
`included
`Symptoms
`_' ·- --~
`nasal congestion, rh inorrhea, red eyes,
`itchy nose/palate/throat, itchy eyes and
`watery eyes.
`
`Ill!!: •
`
`6
`
`PRE OA Y OF
`ENTRY
`
`I
`
`5
`4
`3
`. 2
`DAYS AFTER ENTRY
`
`l l
`~ ~.
`=8
`(f)
`=(f) z
`=:s u
`Cii
`iiiiill>-' :r:
`
`Cl.
`
`8 9
`(f)
`~ 8
`0
`
`zt· <~ 7
`
`UJ>-
`:E (f) 6
`Cl
`UJ z 5
`as
`:E 4 8
`
`'
`
`>
`
`I
`
`~-
`-~ . lll!lliiiiii-
`~ -or
`~ i.tl ~
`
`PROMPT ONSET OF ACTION AND
`INHERENTLY LONG ACTING.
`TELDANE has a rapid onset of action and pharmacokinetic studies show it is inhe,
`·rently long acting. (9,\0) A 60 mg dose of TELDANE shows antihistaminic action for 12
`hours or more. A simple b. d. 60mg tablet gives 24 hour relief of allergic rhinitis symptoms.
`A FIRST FOR AUSTRALIA
`T ELDANE, the first non,sedating H 1 receptor antagonist availab~e in Australia
`.
`g1ves unmatched patient benefits:
`·
`
`N on.-sedating.
`Efficacy equal to conventional antihistamines.
`Fast relief of symptoms.
`No additive effects with alcohol or benzodiazepines.
`Simple and convenient b.d. dosage.
`~1 :in~\ tL l ~in P. Plum~akops1chimria 12:35-44 ( 1979) 2. Data avt~ i lablc <.m n.:qucsr from
`
`REFER ENCES,
`
`w I harn~aceuncals
`J. Be u s T. er. aL /Jr. Mcd.}. 288,28 1-l82 ( 1984 ) 4. Nicholson
`A "N'c,
`1
`Pl.
`· <La · Br. }. Clm. Plutrmacol. 6,J I-J5 ( 1978)
`5. Nicholson AN. ocaL llr. }. Clin.
`u;:nuu:ol. 14,683-90 (1982) 6. Moser L ccaL Eump. }. Clin. PlwTllllu:ol. 14:4 17-23 ( 1978)
`lS I (;1sit ~t.aL Ann. Allergy 54:6 (1985) 8. llackhousc C. L ct. a I Practitioner 226:347-48,
`1
`I J Cl.
`
`E
`"'"'·
`
`'
`
`In,
`
`'
`
`·. ct.aL Eurol>.}. Clin. Plwmuu:ol. 12•195-99( 1977)
`( 1978)
`
`10. 1\cinbergA. cr.aL
`
`Ltd. (I nc. in ACf) f his mat erial w a.s
`at th e NLM and m
`subje-ct us,
`
`® Registered tmdem nrk
`
`APOTEX_AZFL 0061713
`
`DTX-048.001 0
`
`10
`
`

`

`-P r escribing Information- TELDANE (terfenadine) 60 mg tablets--(cid:173)
`Tcrfen;~dine is a histami ne H 1-receptor antagonist with the chemical name 1· (4·( 1, 1-dimethylethyl) phenyl)-4· (4·
`(hydroxydiphcnylmethyl piperidino) -butan-1-ol.
`Tcrfenadine occurs as a white to off-white cryst.allinc powder. It is freely soluble in chloro(onn, soluble in ethanol,
`3 0 d very slightly soluble in water.
`pi{ARMACOLOOY: Tcrfcnadinc, a histamine H - u~ccp10r blocking drug differs phannacologically from conven(cid:173)
`donal antih ista mines regarding its effect on the CNS. Ani mal srudics have demonstrated that at cff'ectivc antihis·
`t3 minic doses. tcrfcnadinc does not cross the blood-brain barrier in sufficient quantity to c.:~we CNS effects. In clin(cid:173)
`Jc:al trials the rcpon:cd frequency of drowsincs.s with tcrfenadinc was similar tu the incidence. of drowsineM with
`placebo. ~~ a~ssmwt in a limit~ .numh:erof he~h~y male volun_teers_hnve.shown no~epres.sam e~ect with sin.gle
`d<»t ad mmutrat Jon of 60 mg. In clln1cal tnals th e mcldfnce of antiCholinergic effects w1th terfenadme were si m1l11r
`to that with convt: ntiona l antihista mint:s.
`1-H~tamint: skin wheal srudies in nonnal volunt~ers have shown that TEL DANE in single and re~ated dos.c:s of 60
`rng hns an antihistamlnic effect beginning at I ·Z hours, reaching ils maximum at 3·1 hours, and lasting for at least
`8 hours after a single dose and for 12 hours after repeated dost1.
`Phannacokinetic studies in healthy ma le subjccu using 14C -Iabelled terfcnadine demorutratr:d that an oral dose: of
`terfen:Kiine Is wd l absorbed from the gastrointestina l tract and rapidly and extensively biorraruformr:d. Following
`administration of a single 60 mg TELDANE tablet detectable plasma levels were obl.trvr:d within one·half hour.
`Phuma leveb peaked a[ about 2 hours after admin istr:Uion: a distribution half- life of 3-1 hours was followed by an
`elimin ation half-life of 20. ) hours. T erfenadinc is extensively (97%) bound to human serum protein. Elimination
`studies with radiolabell ed drug in male volunteers showed that fecal excretion accounttd for 60% of the dos.r: while
`4()% 0 ( the dose was eliminated via the urine. A lmost all of the dose was elim inated in the form of metabolic producu.
`Following -admi nistration of single ~~ of 60 or 180 mg ofTE.LDANE, a linear rcsporue was observed in maximum
`plasma concent ration. Area under the curve (AUC ) calcu lations, however, indic:ne a nearly lour-fold increase in
`reponsc fo r a three-fold increase in dose.
`INDiCATIONS: TELDANE b indic~ted fo r the symptomatic relief of acu te stasona l allergic rhinitis in adults and
`c hildren over ll yeafl of age.
`CONTRA INDICATIONS: TELOANE is contraindicated in patients with a known hypersensitivity to terfenadi ne or
`a ny of its ingredients.
`PRECAUTIONS: Comidenuion should be given to potemial anticholinergic (drying) effects in p:uie:n u with lowe r
`airway di~ase, including asthma.
`USE lN PREGNANCY: Anlm:~l stlKii es have shown no ev1dence of animal teratogenicity. Reproduction studies have
`been ~Xrformed in rats at doses of 150 and )00 mg/kg/day and have revealed decreased pup weight gain and survival
`when tcrfenadinc was administered throughout pregnancy a nd lact:u ion. There arc no adequate and weiJ.contmlled
`studies in pregnant women. TELDANE should be~ during pregnancy only if the potential benefit justifies the
`potentia l rislc to the fttw.
`USI! IN LACTATION: TEL DANE Is not recommended for nu!'ling women. The dmg hasc.awcddecrcased pup weight
`Kaln ami $urvival in rau Riven dose1 of 150 and )00 mg/kw/day throughout prtgnancv and laua tion . Eff~ctl on pups
`exposed to TEL DANE only during lac.uuion are not known, and there are no adequate and well -controlled stutlie1
`In women duri ng lac.tation .
`PAEDlATRICUSE: Safe:ty :md effec ti\leneu olTELOANE In children below thea~e of 12 yean have not been ennblished.
`ADVERSE REACTIONS:! Experience from clinical studies repoued so far, including both cnnttolled and uncontrolled
`
`Merrell Dow
`
`ADVERSE EVENT
`
`studies provides information on adverw: experience incidence: for ~Xti.ods ot a few days up to alx months bee table
`below). The usual dose in th~studie' waJ60 mg twice da ily, but ina small number of patients, thed01e wasas low
`as ZOmg twice a day, or as high as
`ADVIRSE EVENTSREI'ORTEDIN CLINICAL TRIALS
`600mg daily.
`PERCENTOFPATlENTS REPORTING
`<l)NTROllE.DSfUDIES" ALLCLINICAl.~'"TUOIES" '
`In addition to the side effects
`TI~~11~NE Pl~~~BO TE~!rE PL~~~
`reported
`in clinical
`trials (sec
`..•
`table), adverse effects have been
`••
`~~:~.:~:f""\IOU• Synt-m
`reported
`spontaneously
`during
`marketing of TELDANE that war#
`lludxhc-
`6.1 '·' 1.4
`rant lining as possibly :wociatcd
`r~u"'"'"
`with drug administration. These
`Ouunt»
`Nt1Vo1Uw\no
`include: alopecia,
`anaphylaxis,
`:;;:.':~ncn::ut
`angioedema, bronch ospasm, de-
`Catuoin•n•irWSv6l~•
`pression, galactorrhe a, insomnia ,
`Ga.mtmlrMtf\11 O.w~U~
`menstrual di50rders (i nc luding dys:·
`(AMlln•n•ld.w,tM,Na...u.
`menorrhea), musculoslceleral pain ,
`v .. m•• •nc.l..Nncc-on ~lhaho"l
`nightmares, palpitation, p:iires·
`thcsia,
`sweating,
`tachycardia,
`Ey.:, Ear,No.c:andlln'OII
`tremor, urinary frequency, visual
`I,._,.M,>~t~hiNo-'ThR'~•
`~=~"y'
`disturbances and photosensitivity.
`(rm•~"
`In clinical trials, several instances
`Skin
`of mild, or in one case, mode:ratc
`l .O
`transaminase elevations we re seen
`1.6
`1. 7
`1.0
`&urc"wuwud•unx
`. t),.,...,..,,,..,_n!lfi "'CONl""I'.Ol.LfOST\JOIES" •:M~I, l· ' ·~·~~..._.,e.o...nuuol.ool,.
`in patie nts receiving T EL DANE.
`··t~~..,....J,uo~n'~~.-.~LUI""I~LSl\JDitS'w .. ...,,.,;. au~icc choleltatic he
`Mild elevations wc_re also ~c.n in
`titis
`~
`. J I
`placebo tlCatcd paue nu. Forergn markeung expcnences mdudc uolatr:d reporu
`. I
`'
`,
`(.
`and hepat itis: in most case:.s :waii<Jble information is incomplete. In neither the clinaca tna s nor orergn expcncncc
`is a causal relalioruhip of liver abnormalitie1 to TELDANE ua.e clear.
`OVEROOSAGE: One case: of overd053ge has.bcen _reported in a 16 year ol~ fema le whe~ ::;v~5 ':~:~so~ 5~e~~d
`She was 5CCn approximonely one hour after mgcstron and rreated by gastnc lavagh. Had
`.
`.
`ry
`P
`uneventful except for a decrease in BP from 110/60 to 90150 mm Hg two houri a cr , mt~ron.
`. cd
`T re:.tmenr of ovcrdo~ge would r~ason~bly cons.ist of emesis (ipecac syru~~ e~c;~~~~n~~~;~;:~m~~:~~ u:;:
`sciousness, fo llowed by the admir_unrauon of activated charcoa~~h'::.:al ~line. Saline cathartics may al$0 be of
`ces.sfu l, or contraindic:ued, gaunc lavage 1hould be: perfonned _
`. d " 1 bl
`.
`value for rapid dilut ion of the bowel contents. lr is not known 1f terfcnadt~c "
`ta Y13 ~·
`Treatment of the signs and !iymptoms of overdosage should be symptomattc and supportive after the acut~ itagc.
`tcr than 5()(X) mglkg in mature mice and rats. The oral LOsowaJ 438 meflcg
`·
`Or-al LDso value' for terfcnadme w~re grea
`mended therapeutic dose in adults have bee.n
`.
`(600
`) h
`in newborn rat!i. Si ngle doses as h 1gh ;u: ten t1mes
`mg t e rcc.om
`sua I dosage for adults ~nd children l l years and older is 60 mg ( I tablet)
`TION Th
`well tolerated.
`e u
`DOSAGE AND AOMINISTRA
`:
`( 20 Ea h TELDANE hi
`h'
`·
`"
`·
`·
`rwiculaily.
`PRESENTATION: TELDANE tablets are ava ilable in blister strips m. pac~;s g
`,:
`ta et 1s w 1~e,
`c
`round, Oat faced and bevel edged with "M" on one side and a break I me and 081 o n the other. Each tablet conta ins
`60 mg tc rfenadinc .
`
`0, 1
`7.4
`0.9
`1.1
`O.l
`0.6
`o.o
`
`J.O
`
`1.8
`0.!
`0.)
`0.8
`
`15.8
`4.5
`I. I
`1.7
`0.6
`0.!
`
`7.6
`
`4.8
`1.5
`).1
`0.7
`
`0.1
`11.1
`1.0
`l.l
`1.0
`0.1
`0.0
`
`1.4
`
`) . I
`1.7
`1. 6
`0.4
`
`0.9
`0.9
`0.6
`
`• . 6
`
`1.)
`0.9
`o.s
`o.o
`
`. h ,
`
`s~ . M'n//;hAJ:,,~
`'"" mo • ,,:'J..::::-"""r"'
`-:;tree
`
`Product mformauon as of February, 1986
`
`Merrell Dow Pharm.1ccuucal• Awtrn11PPt}~fa Nne. ma.R~5J~ificr Street, North Sydney NSW l060.
`Subj e<t USCopynght Law s
`
`etltt\teertd tr1ldHnaR
`
`3 -
`
`APOTEX_AZFL 0061714
`
`DTX-048.0011
`
`11
`
`

`

`ISOPTIN®
`The antihypertensive. Because you want
`antihypertensive effect, not side-effects.
`PRESCRIBING INFORMATION
`VERAPAM IL HYDROCH LORIDE
`Indications:
`I Hypertension
`I Angina of effort
`• Angina at reSt
`I Vasospmic angina (including Pronzmctal's vanant angona)
`I TachyarrhythmiJs including parox ysmalsupra·vCntricular tachycardoa
`I Atrial fibrollation }
`.
`w1th rapid vcntricull r response
`• Atrial flutter
`Use in Pregnancy:
`Only limited information is avaolablc on the usc of ISOPTIN on pregnancy
`The drug should therefore not be used in pregnant womcn.or those lokely to
`occome pregnant, unless the expected benefots outweogh any potentiJI rosks
`Use in Lactation:
`The usc of ISOPTIN during lactation should be avoided unless cxpeetcd
`benefits outweigh any potential risk . Howe.,.er. preliminary results indicate
`thlt vcrapamil may reach concentrations of 10-6S ng ml in the milk' of
`nursmg mothers. Such conccntrauons arc unl1kcly w produce climcal
`effcm in the infant .
`CONTRAINDICATIONS:
`Cardiogcnoc shock
`Rcccm myocardial1nfarction
`Known hypcrscnsitivily to vcrapamd hydrochlondc. or to asp1nn or aro
`dyes, s.incc the oral formulations contain tartrazinc.
`WARNING:
`Use vcrapamol hydrochloride with caution in con1unction with beta
`adrenergic blockmg drugs Js the myocilrdial depressant effects of each drug
`maybe additive .
`PRECAUTIONS:
`In sick-sonussyndrome and second and thord degree heart block.
`ISOPTIN may furthc rimpairSA or AV nodal funCtion respeCtively.
`In the presence of cardiac fa oiOJrc lull compensation with cardiac
`glycosidcs should be ensured prior to administration of ISOPTIN.
`Caution is necessary in 1mt1Jt1ng treatment. or •ncr easing dosage of
`ISOPTIN in patients with ccrebrovascularacctdents. smus bradycardia.
`he an block and hypmcnsion.
`INTERACTIONS:
`Both ISOPTIN and beta blockong drugs may slow AV conduction and depress
`myocardia\ contractility by different mechanisms. Cardiac function. bean
`ra(c and rhythm. and blood pressu re should be closely monitored dunng
`Simultaneous oral adrn1nistrauon .
`Other am1·arrhythm1C , am•·hyperrc:ns1vc and cardiodcprcssant drug
`therapy should be revocwed pro or to oncroduc to on of ISOPTIN .
`ISOPTIN has been reported to increase plasma levels of digoxon .
`Physic 1ansshould be alert for symptoms of possible digitalis lntoxica.tion.
`1nd may wish to measure digox1n levels in plasma . However. extenstvc
`experience mdicates that th•s posstble inter acuon is of only slight clinical
`relevance.
`DOSAGE AND ADMINISTRATION:
`In mold and moderate hyperten~on the usual starting dose osonc 80mg
`tablet two or three tomes 1 day The maintenance dose may be adjusted to
`two 80mg tablets two or three times a d,ly.
`Usual maintenance dose 160 mg twice daily.
`The ondivodual dose and frequency of dosing. should be dctermoncd on
`accordance wtth the mdKatlon and individual patient response .
`Paediatric:
`Dose range 40-360 mg per day in 2 or 3 divided daoly
`doses according to age and response .
`The recommended daily dosage
`os usually well tolerated .
`Ca.ution should be excrc1sed when 101t1ating therapy
`since the pharmacological action of ISOPTIN may be
`increased or prolonged by hepatic insulficocncy
`ADVERSE REACTIONS:
`ISOPTIN is usually well tolerated.
`More common reactions incllJd~ constipation. flush. headache and
`dizzmess.
`Hypotension, bradycardia. development or worsening of ~ymproms of
`cardiac fa1lure and rhythm disturbances have been repon ed.
`Rarely, non-specific immunological reactions such as ski n rashes may occuc
`lndovidual hypersensitivity to verapamil in the absence of accumulauon or
`o'erdosagc, has been dcscnbcd.
`OVERDOSAGE:
`Symptoms: Bradycardia, cardiac arrest. second and third degree AV
`block. hypotension and myocardial insufficiency.
`Treatment: Serious oral overdosage should be treated by onduced
`emesis, or gastric lavage and aspiration. prior to admission to 1ntCns1vc
`care.
`Repeated intravenous calcium gluconatc (10 mi. 10°o solution). and
`sodium bicarbonate if metabolic acidosis develops rc prcsem logical
`therapy.
`Intravenous fluids and cardiorespiratory support may be 11ecessary.
`Doalysis would not seem potentially useful.
`Other treatment. selected in accordance with the presenung symptoms.
`may include atropine, isoprenaline (isoproterenol), dopamine, cardiac
`g!ycosidcs and noradrenaline (norepinephrine).
`Recorded overdoses survived include a H year old g~rl who ingested
`H g and a 28 year old woman who took 5.6g.
`PRESENTATION:
`ISOPTIN 40mg 1100 tablets) NHSGeneral Benefi t - 100 tablets. 5 repeats
`ISOPTIN 80mg (100 tablets) NHS General Benefi t- 100 tablets, 5 repeats
`ISOPTIN 160 mg (60 tablets) NHS General Benefit - 60 tablets, 5 rcpem
`full Prcscnbong Information avaolablc on request.
`
`}
`Geria(ric
`Renal faolurc·
`HepatiC fao lurc:
`
`0 Distributors: Knoll Pharma Division, Schcring Pty l omitcd
`
`knoll (Inc in NSW) 9- 10 Wood Street Tempe NSW 2044 Australia
`
`isopt•n • is a r~g1nercd trJde mark of Knoll AG. the p1oncen of cak1um amagon1\m
`
`. . . Fixed Drug Combinations
`
`atropine in each tablet. The rationale is that the un(cid:173)
`pleasant anticholinergic side effects of atropine would
`discourage anyone from taking an excess of tablets on
`more than one occasion. Whether this is a successful
`ploy is not really known since habituation has not
`been reported with usual therapeutic doses [7]. Fur(cid:173)
`thermore, it does have some disadvantages as over(cid:173)
`dosage in young children has resulted in atropine poi(cid:173)
`soning as well as severe respiratory depression [8].
`
`Cost
`
`The factors determining the costs of therapeutic
`drugs are complex and vary from country to country
`and from time to time. It is virtually impossible to
`do all the sums taking into account the costs of pre(cid:173)
`scription and dispensing fees and government rebates.
`Overall it is probable that combination products are
`cheaper than the individual components prescribed
`separately but there is evidence both for [6] and against
`this view [9].
`
`Potential Disadvantages of Fixed
`Drug Combinations
`
`There is an almost equal number of theoretical dis(cid:173)
`advantages to fixed combination drugs as shown m
`table II.
`
`Fixed Dose Ratio
`
`One of the major problems is that the prescribing
`doctor loses flexibility in patient management. For
`
`Table 11.
`Potential disadvantages of fixed drug
`combinations
`
`l
`
`Fixed dosage ratio (inflexibility)
`
`Incompatible pharmacokinetics
`
`Increased toxicity
`
`Inappropriate combinations
`
`Physician ignorance of content
`
`Brand names
`
`22
`
`CURRENT THERAPEUTI CS DECEMBER 1986
`
`This mat er ial w ascopi!!i:l
`
`APOTEX_AZFL 0061715
`
`DTX-048.0012
`
`12
`
`

`

`... Fixed Drug Combinations
`
`many drugs such as insulin or 13-blockers the effective
`dose varies between patients and in different disease
`states, e.g. in hepatic or renal failure, doses of many
`drugs must be carefully adjusted. It is not sufficient
`to defend fixed drug combinations by saying that many
`doctors do not adjust doses anyway and do not have
`the knowledge of pharmacokinetics to do so accu(cid:173)
`rately. Bad prescribing cannot be justified by igno(cid:173)
`rance, rather it is an argument for improving doctors'
`knowledge of clinical pharmacology.
`
`Incompatible Pharmacokinetics
`
`Some combination drugs such as co-trimoxazole
`have their components deliberately selected to have
`similar half-lives and clearance rates. This is not the
`case with many other combinations, particularly the
`older ones, and this can produce very different pat(cid:173)
`terns of drug accumulation [I]. If the 2 component
`drugs are prescribed separately there is scope for dif(cid:173)
`ferent dosage intervals. However, sometimes phar(cid:173)
`macokinetic differences are irrelevant as il) the case
`of 13-blockers and diuretics where biological effect is
`quite different from half-life. Sometimes it could even
`be advantageous to have 2 drugs such as analgesics
`with differing onsets and durations of actions.
`
`Increased Toxicity
`
`The use of 2 drugs will always increase the risk of
`adverse drug reactions both idiosyncratic and phar(cid:173)
`macological. The problem with combination drugs is
`trying to decide which of the 2 (or more) components
`has caused the problem. If both have to be stopped
`t