pharmaceutical Medicine
`
`Volume 1 Number 4 February 1987
`
`Contents
`
`gJJJTUARY
`
`------
`
`EDITORIALS
`
`coMMENTARY
`
`253 William L. Burland MB, ChB, DCH,
`Dip Pharm Med
`
`255 Measuring the Impact of the Restricted Drug
`Formulary
`258 Rules of Sponsorship . . . . ..
`261
`Safeguards for Healthy Volunteers
`
`265 Getting the Best out of Therapeutic Trials
`267 Widening the Use of Established Medicines
`267
`Irish Volunteers
`268
`Start .... BrAPP .... Stop
`270 The Bad News
`Society of Pharmaceutical Medicine
`270
`270 Dr Bill Burland
`
`PAPERS
`R. V. Lewis, P.R. Jackson &
`L.E.Ramsay
`
`273 Visual Analogue Scales for Side-Effects of
`Beta-Adrenoceptor
`Blocking
`Drugs:
`Reproducibility of Scoring
`
`R. N. Davidson, A. Allistone,
`P. S. Richardson &
`K. B. Saunders
`
`279 A Comparison of Body Plethysmography
`and a Forced Oscillation Technique (Siemens
`Siregnost FD5) in Studies of Broncho(cid:173)
`constriction
`
`J. Woodman, R. J. Shaw,
`A. J. Shipman &
`A. M. Edwards
`
`289 A Surveillance Programme on a Long(cid:173)
`Established Product: Imferon (Iron Dextran
`BP)
`
`OCCASIONAL LECTURE
`B.Durie
`
`POINT OF VIEW
`C. S.Good
`
`297 Why do They Always Print the Bad News?
`
`303 Cooperation
`between Companies
`Planning Comparative Clinical Trials
`Continued overleaf
`
`in
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 1
`
`

`

`Editor
`Robert N.Smith MD FRCP
`Director of the J\,frJical Dir is ion, Glaxo Group Rc.,·earch
`l,imitetl, (ireenjiml, [JK;
`/imnerly Senior l.c•c/urer and
`Consultant Physician, C/ini,:ul Pluirmawlo{;y and
`Tlterape111ics, Unfrcr.,ity of Slte{fit'ld
`
`Assistant Editor
`Peter J.Kcen MPS
`Clini<:ul Research Serl'i,·c.r, G/axo Grnup lfrsearch
`limited. Grcenji,rd. (..i K
`
`Editorial Advisory Board
`Daniel L.AzarnoffMD FACP
`Presidenl. Res<'ard, and De\'elopmc11r. GD S,•arle &.
`Comp1mr. Chic-t1go. USA:
`formerly Pro/i•ssor 11(
`Medicine and Plwmwcoloi.;y. Unil'ersi/y 11( Kw1.rns
`Afctfiail Cimrcr
`Michael G,Carter MB BPharm
`Head ofh11erna1iona! Affairs. Imperial Chemical
`lml11slrie s pie, M11cdqfic/d, UK;
`fomwr/1· Director of
`Pharmw:emirnl Di,i,im1. Ro!'he Prod11cts limited,
`fVc/1,·y11 Garden City
`J.Desmond Fitzgerald MD FRCP
`Medi~al Director, impaial Cltemirnl 111,l!mries pie.
`Macclesfield, [JK;
`jim11erl_1· Professor 00lfrdici11e.
`Mm:Afosler Unircr.,·itv. Hamilton. 011/ario
`Sir Abraham Goldberg MD FRCP
`Regius Profes.wr CJ/ thr. l'rac1iee <if',l\4cdi,:ine. Ulliversily
`o(Glu.ff(<M, UK;
`Chairman, Commirlee on Safi-ty olAf,,Jicines
`Arthur H.Hayes, Jr., MD
`Demimui Proms/. New York Medical Col/egt', Nell' York
`Ciry, USA: .frirmerl_r FDA Cmnmisi-i,mer. Washington DC
`Inga Lunde MPhann
`Con.mlta/11, Ji'or!d Health Orga11i;11/ion, Regional Olftce
`for Europe, Copenliagl'll;
`formerly Medical Din·ctor,
`M,.rck Sharr ef<c Do/1111e. Norway
`William P.Maclay MB DTM&H
`Direcwr of Medical Afji,irs. Smu/o; Prod11ds Limited,
`Lmu/011, iJ K
`..
`Cyril Maxwell MB ChB
`Mcdic·al Direcwr 1111d Chief Exernliff, Clinical Research
`Servii'es Limited. London.· UK:
`(ormcrlv Metlinil
`·
`Director, Richardson-Mare/I Li1i1i1ed
`Derck C.Quantock PhD MD
`Dircczor of Science and Technology, Fi.Wm Limiled,
`fomwr/y Medi<:11/ Directur,
`Loughborough. UK:
`A.uodar/0110(1/tc British Plwrnwceutical ludaszrv
`Peter S.Schonhofer MD
`.
`IHstitutefiir Klinisdie Pltwmako/ogie.
`Zentralkra11ke11lwus. Bremen, F.R. Gemumv: {,,mwrlv
`Rese11r1:h Coordina1i,m, J11sti1111e(iir Ar:miinirrel.
`-
`Bundesgcstmdheil.rnm I, Berli11
`Julian H. Shelley BSc MRCP
`Hem! of Medical Reseurch. Boehri11ga Jngdhcim
`]111emalimwlGmbH, Brnclwe/1, UK; Visi1/11g Le<:111rcr
`in Pharmacology, King's College, Lo11d,m
`Paul Turner MD FRCP
`Prolessor ,f Cli11iml Pham1ac·ology, St Bar1/wloml'\I' 's
`Ho.rpital /l/1!1/lml Col/cg,•, Lomlo11. UK
`Geoffrey R.Venning BM FRCP
`Director 11( Reuard1 and De\'e/opmelll, Janssen
`formerli·
`Plwrmace111iwl Limited, Gr11\'e, Wan/age, UK;
`Senior Ml'clical 0,/ficl!r. /Hedil'illt!S Division. DHSS
`·
`William M .Wardcll DM DPhil
`Vice-Prcside111/Medic:11I Dire,:tor. Boehringer lngdl,eim.
`Ridg~(ield, USA ;
`f,wmerly Associate Professor o(
`Plwrmaco/ogy and Assisla11/ Profi's,>11r of Medicine <111</
`Diret"/or, Ce11ter for the S111<(v o(Dmg De,·cloplil<'III.
`University o(Roc/1e.11er Afrrlirnl Cc111u
`
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`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 2
`
`

`

`p}wrmaceut. Med. ( 1987), 1, 289-296
`
`A Surveillance Programme on a Long•established Product:
`{mferon (Iron Dextran BP)
`
`John Woodman 1, Richard J. Shaw\ A. John Shipman3 & Alan M. Edwards4
`
`'Manager, International Drug Surveillance, 'Drug SLlrveillance Associate and 'Director or Medical
`Affairs, Department of Medical Affairs, Research & Development Laboratories, Fisons pie,
`pharmaceutical Division, Bakewell Road, Loughborough, Leicestershire LEll ORH, UK and
`jMcdical Adviser, Roche Pruducls Ltd, PO Box 8, Welwyn Garden City, Hertfordshire AL 7 3A Y, UK
`
`1 A year-long post-marketing surveillance programme was conducted on
`Tmferon (iron dextran BP) thirty years after it was introduced.
`2 Records were obtained on 1260 patients treated by total-dose infusion, an
`estimated 23% of total U.K. usage; 91 % of patients were women and of these
`72% were pregnant.
`3 The overall reaction rate was 29.8%, with 14.3% immediate reactions
`occurring on the day of infusion and 17. 7% delayed reactions occurring on later
`days; 2.1 % of patients experienced both immediate and delayed reactions.
`Severe reactions were recorded in 5.3% of patients.
`4 A range of immediate symptoms suggestive of hypersensilivity were
`recorded, whereas the predominant delayed symptom was arthralgia.
`
`Introduction
`
`Jmferon® (iron dextran injection BP) is an iron dextran complex which is
`administered parenterally for the treatment of iron deficiency anaemia. Its
`administration by intramuscular injection was first described in 19541 and
`subsequently it became used to a limited extent by intravenous injection. Imferon is
`the only iron complex in therapeutic use with sufficiently low levels of loosely bound
`iron for safe intravenous administration. Because of the practical difficulties of
`giving large volumes by direct intravenous injection, the technique of total dose
`infusion (subsequently referred to as TDI) was introduced in 1963.~ In this
`technique, the total dose of iron which the patient requires as iron dextran is diluted
`in saline or dextrose and given as a slow continuous intravenous infusion usually
`over a period of several hours.
`The level of reactions to Imf eron reported to Fisons pk remained very low for
`many years, probably because of their familiarity to regular users and because of the
`generally low level of reporting from developing countries. This picture changed
`during 1981 and 1982, when reports began to be received from both developed and
`developing countries of a considerable increase in the incidence of delayed reactions,
`in which arthralgia and pyrexia were the predominant features. Strong
`circumstantial evidence linked this marked increase in incidence to the release into
`the market oflmferon made from late 1980 onwards by a manufacturing process to
`©The Macmillan Press Ltd 1987
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 3
`
`

`

`290
`
`J. WOODMAN el al.
`
`which a number of relatively minor amendments had been made in order to keep
`pace with developments in pharmaceutical production techniques. The product
`made by the amended process was completely satisfactory in terms of analytical and
`pharmacopoeia! specification both before release and on subsequent retesting.
`Extensive investigations failed to reveal any cause for the apparent difference in
`reaction rate. Production oflmferon by the amended process was suspended and the
`decision was taken to return without delay as nearly as possible to the original
`process. It was clear that a systematic collection of information on the safety of the
`newly produced material would be necessary. It was decided to use a specialised
`approach to post-marketing surveillance in the United Kingdom to achieve this.
`This paper describes the methods which were used and the results which were
`obtained.
`Post-marketing surveillance is one of the tools used in the first years of marketing
`to confirm or to modify the adverse reaction profile of products established in pre(cid:173)
`marketing clinical trials. A number of approaches to post-marketing surveillance
`have been used in recent years, most of them involving the recruitment of interested
`clinicians and detailed documentation of response to the product. This approach
`would have been inappropriate to the confirmation of the safety of newly produced
`Jmferon. The frequency of use by any one clinician is relatively low, and it was felt
`inappropriate in the unusual circumstances to encourage Imferon usage in any way
`by specific recruitment. The approach chosen was to attempt to collect limited
`information on the routine use of the product from as many users as possible.
`
`Methods
`
`A letter was sent to all likely UK users of the product (obstetricians, gynaecologists,
`haematologists, geriatricians and general physicians) announcing the availability
`once again oflmferon made by the original process, reminding them of the reactions
`which had occurred and requesting their cooperation in what was described as the
`Imferon Surveillance Programme. A similar letter was sent to all hospital
`pharmacists, drug information pharmacists and regional pharmaceutical officers
`with the addition of a pad of three-part record cards. Hospital pharmacists were
`requested to ensure that a three-part card would be supplied with each prepared
`Imferon infusion leaving the Pharmacy, or a supply of cards would be sent with each
`box of Imferon ampoules going to the wards. The aim of the record cards was to
`elicit essential information on the patient and the degree of anaemia, and to record
`the amount of Imferon given, the diluent used, any previous exposure to Imferon
`and any symptoms that were associated with the administration of Imferon. The
`first of the three parts was to be completed on the day of infusion to record whether
`or not immediate symptoms were seen and to give an estimate of severity (mild,
`moderate or severe). The second part was to be completed one week after infusion
`for inpatients, or at the next clinic visit for outpatients, to provide similar
`information on any delayed symptoms. The third part was to be retained with the
`patient's notes to highlight the giving of lmferon and to facilitate any subsequent
`questioning. Parts 1 and 2 were pre-gummed cards which were to be sealed and
`returned to Fisons post-paid immediately after completion.
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 4
`
`

`

`JMFERON SURVEILLANCE PROGRAMME
`
`291
`
`The method of surveillance was very simple, but it was designed to obtain widely
`based information on the normal usage of the product. There was no recruitment of
`users, no payment or other inducement for the completion of record cards and no
`involvement of the sales force. The surveillance programme began in April 1984,
`coinciding exactly with the introduction of the newly produced material after a
`period of several months duringwhich the 20 ml ampoule used for TOI had not been
`available. The programme ran for one year. The end of the programme was
`announced in a mailing to all doctors and pharmacists who had returned completed
`record cards during the year.
`
`Results
`
`The results of the Imferon Surveillance Programme can be considered first in terms
`of the response to the programme and then in terms of the information generated on
`adverse reactions associated with the product. The response can be assessed by the
`number of records returned, the number of hospitals participating and the amount
`oflmferon used. During the year of the programme, the total number of patients for
`whom full records were received was 1260. Patient records were not entered into the
`results unless adequately completed cards were obtained for both the day of infusion
`and for the subsequent follow-up. The monthly rate of return showed some
`fluctuation: predictably the lowest return was in the first month (52 patients) and
`thereafter the maximum was 138 patients in the eighth month, the lowest 83 in the
`tenth. The mean monthly rate of return was 105. These 1260 completed records were
`received from 247 hospitals throughout the UK. However, I 00 hospitals accounted
`for only a single patient record and so the remaining 147 hospitals accounted for
`1160 patients. The maximum number from one hospital was 66, with 26 hospitals
`returning IO or more records.
`Imferon administration by TDI is entirely a hospital procedure and there is no
`realistic way of recording accurately how often it is performed. Some
`approximation of usage is possible through analysis of sales of the 20 ml ampoules
`used exclusively for this purpose. For the period of the surveillance programme, it is
`probable that an average of just over 400 infusions was given in each month, giving a
`total of approximately 5000 patients infused for the year. The 1260 patients for
`whom completed records were received therefore represents a notional response rate
`of around 25%.
`The patient population for which records were received was overwhelmingly
`female (1150, 91 %). Of these women, 837 (73%) were pregnant. This high
`proportion may mirror accurately the overall usage of Imferon in the UK, or it may
`have been influenced by high reporting rates from a relatively small number of
`obstetric units. Because of the preponderance of pregnant women, mostly aged
`under 30, there was a significant difference in age distribution between women
`(mean 32, range 2-99 years) and men (mean 59, range 1-91 years). For both sexes,
`the degree of iron deficiency anaemia as measured by the last recorded haemoglobin
`level was relatively mild (mean 9.2, range 4.1-14.4 g/dl).
`The information collected on reactions associated with Imferon TDI will be
`
`PGR2020-00009
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`Petitioner Ex. 1088 - Page 5
`
`

`

`292
`
`J. WOODMAN et al.
`
`considered first in terms of reaction rates and then the individual symptoms. Any
`symptoms occurring within 24 h of the start of Imferon infusion have been defined
`as an immediate reaction, any later symptoms defined as a delayed reaction. The
`reaction rates for six groups - all patients, men, women, pregnant and non-pregnant
`women and for all patients except pregnant women - are presented in Figure 1. It is
`clear that the proportion of patients experiencing no reaction to Imferon is
`remarkably constant across all groups, with an overall value of7O.2% and a range
`of only 69% for pregnant women compared to 74% for men.
`For immediate reactions, the rates are also very constant, ranging from 13.6 to
`16.6% with an overall rate of 14.3%. There is slightly more variation for the level of
`delayed reactions, with a range from 11.3% in the relatively small sample of men to
`19.4% in the pregnant women, and an overall rate of 17.7%. A small proportion
`(2.1 % ) of patients experienced both immediate and delayed reactions.
`The severity of the reactions is presented, again by patient group, for immediate
`reactions in Figure 2 and delayed reactions in Figure 3. It was clear from the record
`cards that there had been variable use of the severity classification by different
`reporters. Some had used it as a global assessment of the clinical significance of the
`symptoms observed and others had used it to indicate simply the severity of the
`symptom. For example, the classification 'severe' was applied to a full-scale
`anaphylactoid reaction in one patient and to headache in another. This variability is
`inherent in all but the most highly structured methods of event recording, and was
`unavoidable within the limits of this simple surveillance programme. For all
`patients, the values for mild, moderate and severe immediate reactions were 7. 7, 3.8
`and 2.8%; for delayed reactions, the corresponding values were 7.1, 8.0 and 2.5%.
`Again there was very little variation in the values for different groups. There was no
`correlation between the overall reaction rate or severity and possible factors such as
`
`ao
`
`70
`
`00
`
`(1)
`~ 50
`c
`(1)
`'-'
`;;, 40
`0...
`
`30
`
`?O
`
`1G
`
`pJ tfGnts
`
`'Nomen
`
`Non
`pregnJ~t
`\\·an10n
`
`1111 oa1ienLs
`cxrnpl pregnart
`v,,.::,;,rner
`
`Figure 1 Reaction rate by patient group !881No reaction; ~Immediate reaction; [l[] Delayed reaction
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 6
`
`

`

`IM FERON SURVEILLANCE PROGRAMME
`
`293
`
`10
`
`C: g
`~ 6
`QJ a:
`
`4
`
`All
`patients
`
`Men
`
`All
`women
`
`PrcgnJn:
`women
`
`Non pregnant All patients
`1,,vomeri
`8Xt:Cpt pregnant
`women
`
`Figure 2
`
`Immediate reaction severity by patient group 1881 Mild; 00 Moderate; III!I Severe
`
`the patient's age, last recorded haemoglobin level and the volume oflmferon given.
`The free text descriptions from the record cards were transformed for analysis
`into a standardised vocabulary of symptoms based on the WHO list of preferred
`terms. Table 1 presents a listing of both immediate and delayed symptoms by WHO
`body systems. For immediate symptoms, well over half were in only three body
`systems: central and peripheral nervous, where dizziness, nausea and headache
`accounted for most reports; respiratory, with chest pain, dyspnoea and
`
`10
`
`9
`
`8
`
`* 7,
`"' '§
`
`C: 6
`0
`·.;:,
`u IB s
`c:::
`
`4
`
`3
`
`patients
`
`Men
`
`women
`
`nregnan-:
`
`e.::xcep-: prngnunl
`v~'omun
`
`Figure 3 Delayed reaction severity by patient group ~ Mild; Im Moderate; []IIJ Severe
`
`PGR2020-00009
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`

`294
`
`J. WOODMAN eta!.
`
`Table}
`
`Immediate and delayed symptoms by body system
`
`Body system
`
`Skin and appendages
`M usculoskeletal
`Central and peripheral nervous
`Vision
`Gastrointestinal tract
`Cardiovascular general
`Heart rate and rhythm
`Vascular (extracardiac)
`Respiratory
`White cell and RES
`Female reproductive
`Foetal disorders
`Body as a whole
`Application site
`
`Immediate s.vmptoms
`(%)
`
`Delayed srmptoms
`(%)
`
`9.3
`9.8
`19.9
`0.5
`5.5
`6.0
`6.0
`7.4
`18.6
`
`0.3
`]4.8
`1.9
`
`6.8
`46.4
`13.4
`0.5
`7.7
`1.1
`0.5
`0.3
`2.2
`0.3
`LI
`0.5
`14.2
`4.9
`
`bronchospasm and cyanosis most common; and the body as a whole, where pyrexia
`was by far the commonest symptom. Other symptoms occurring frequently were
`flushing, tachycardia, hypotension, arthralgia, back pain, urticaria, rash and
`pruritus, vomiting and infusion-site phlebitis. The term 'anaphylactic reaction' was
`used only three times, but all three reactions were severe. No fatal reactions were
`reported.
`The overall impression from the record cards is that Imferon produces a wide
`variety of symptoms suggestive of immediate hypersensitivity, but that these
`symptoms are not often severe. Certainly a full-scale anaphylactoid reaction is rare:
`an approximate incidence of 1.83% is obtained if the three specific reports are
`combined with the 'severe' reports of symptoms such as bronchospasm, cyanosis,
`dyspnoea, hypotension and shock. An unexpected finding was the frequency with
`which pain in a number of sites (back, leg, abdomen, chest, loin) was reported.
`Almost half of the delayed symptoms were musculoskeletal. Within this group,
`almost all were arthralgia, with small numbers of reports of myalgia and back pain.
`The only other symptoms seen with any frequency were dizziness, headache, nausea,
`vomiting, pyrexia, urticaria, rash and infusion-site phlebitis. T he pattern of delayed
`symptoms was thus much as expected; and was clearly differentiated from the
`immediate symptoms. The time of onset of delayed symptoms was usually within
`the first 3 days after infusion, but could be as late as 9 days. The duration of delayed
`symptoms ranged from 1 to l O days, with a mean of 4 days.
`
`Discussion
`
`These results show that it is possible to carry out successfully a surveillance
`programme on a product some thirty years after marketing. The notional 25%
`response rate, with no recruitment, and the steady rate of return of records during
`the year suggests a degree of commitment to the product among users, and that the
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1088 - Page 8
`
`

`

`IMFERONSURVEILLANCE PROGRAMME
`
`295
`
`requirements of the programme were not judged to be onerous. The great similarity
`of reaction rates among patient groups and the constancy of reaction rates reported
`throughout the year encourage the belief that the results of the programme give a
`reasonably accurate picture of the way Imferon is used in British hospitals and of the
`reactions it causes. The overall picture which emerges is of a product widely but, in
`most hospitals, relatively infrequently used, with its major indication being the
`anaemia of late pregnancy. The reaction rate for all patient groups is around 30%,
`with a roughly equal split between immediate and delayed symptoms, and a few
`patients experiencing both. Severe reactions are seen in 5.3% of patients. There is no
`way of knowing whether these reaction rates are truly representative of the total
`experience, and it is possible that either there was selective under-reporting of
`reactors or, perhaps inherently more probable, of non-reactors.
`[mferon has long been recognised as causing a variety of adverse effects. These
`may be divided into two categories, immediate reactions, which occur during or
`soon after administration, and delayed reactions, which occur on subsequent days.
`Most published reports of immediate reactions have emphasised their apparent
`anaphylactoid nature, with symptoms of tachycardia, hypotension, dyspnoea and
`cyanosis. The delayed reactions consist predominantly of joint and muscle pain,
`often accompanied by mild pyrexia and occasionally by lymphadenopathy.-1 7 In
`most cases, reports are of mild reactions, but immediate life-threatening reactions
`may occur. In a large series of 481 patients treated over an 8-year period, the inci(cid:173)
`dence of such severe reactions was 0.6%.4 Fatal anaphylactoid reactions have occur(cid:173)
`red rarely after both intramuscular~ and intravenous use.9 In the largest published
`series of patients treated with Imferon TDI, there were no fatal reactions in 5500
`patients. 10 The incidence of reactions to Imferon described in published reports has
`varied greatly, ranging from none in 133 African patients11 or 124 Mexican
`patients, 12 to 100% in 80 patients in lndia. 13 Reports from the Indian sub-continent
`have been characterised by a high incidence of reactions, suggesting that ethnic
`factors may be involved. In large studies from other territories, incidences ranged
`from 1.5% to I 9.2% .4
`16 The wide variation in reaction rate, even in similar
`10
`14
`·'·
`•
`-
`populations, suggests that there may be some local factor, possibly unrelated to the
`product, but there has been very little investigation of the mechanism of either the
`immediate, or the delayed reaction.
`In a recently completed prospective study in pregnant women in Tanzania,17 the
`immediate reaction rate was slightly lower (6.1 %) than that observed in this
`programme but the delayed reaction rate was very similar (19.9%). The symptoms
`recorded during the programme are largely as expected from previous published
`and unpublished experience with a clear differentiation between immediate and
`delayed symptoms.
`Considerations of overall risk and benefit are outside the scope of this report.
`However, from the information collected during the year of the programme it
`appears that, in the view of British users, Imferon made by the current production
`process performs adequately.
`
`We acknowledge the excellent administration of the programme by Cynthia Hallam and the assistance
`of Jane Rogers with data collection.
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`2%
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`J. WOODMAN i'I al.
`
`References
`
`1 Baird IM & Podmore DA. Intramuscular iron therapy in iron-deficiency anaemia. Lancet 1954; 2:
`942.
`Basu SK Rapid administration of iron-dextran in late pregnancy. Lancet 1963; 1: 1430.
`' Freed N. Intravenous iron replacement: indications and safety. Journal of the American Osteopathic
`A ssodation 1982; 82: 115.
`4 Hamstra RD, Block M H & Schocket AL. Intravenous iron-dextran in clinical medicine. JAMA
`1980; 243: 1726.
`5 Kuah KB. Total dose infusion of Imferon in obstetrics. Medical Journal of Malaya 1972; 26: 186.
`• Mehta BC & Patel JC. Iron-dcx:tran total dose infusion in the treatment of iron deficiency anaemia.
`Indian Journal or Medical Sciences 1968; 22: 1.
`7 Mehta BC, Jhaveri K & Patel JC. Total dose iron therapy using iron-dex:tran. A study or 514 cases
`using different techniques. Indian Journal <f Medical Sciences 1970; 24: 191.
`' Becker CE Fatal anaphylaxis after intramuscular iron-dextran. Annals of Internal Medicine 1966;
`65: 745.
`' ZipfR E. Fetal anaphylaxis after intravenous iron-dextran. Journal of Forensic Science 1975; 20: 326.
`1° Fahmy K. Systemic reactions with total dose infusion of iron dextran complex in ohstetric patients.
`Imernational Journal of Gynaecology and Ofotetrics 1978; 16: 170.
`'' Jenkinson D. Single dose intra-muscular iron-dcx:tran in pregnancy for anaemia prevention in urhan
`Zambia. Journal of Tropical Medicine and Hygiene 1984; 87: 71.
`,: Loria A, Cordourier E, Arroyo P, Piedras J & Medal LS. Nutritional anaemia. JV. Effect of single
`intravenous dose of iron-dextran in prevention ofhypoferremic anaemia of pregna11cy. Re1,ista de
`Jmestigac:ion Clinica 1972; 24: 113.
`'-' Mittal MM, Bhargava SP & Sharma ML Treatment of 80 cases of iron deficiency anaemias by
`TD! of iron-dcxtran complex. Journal of the Association of Physicia11s of India 1969; 17: 45.
`" Tharmaratnam A, Vikraman P & Kanagalingam N. The use of Jmfcron (iron-dcxtran) as a total
`dose infusion. Medical Journal or iWalara 1967; 21: 319.
`15 Pathak UN, Wood J K & Sorhaindo B A .. Anaemia in pregnancy treated with a single intravenous
`dose of iron dextran. Obstetrics and Gynaecology 1967; 29: 500.
`"' Mans on I W. Total dose infusion with iron dcxtran complex in pregnancy and the puerperi um.
`Meclic·al Journal of Australia 1966: 1: 174.
`17 Kaisi M, Ngwalle KEW, Rogers J J & Stevens MT. lmernational Journal of Gynaernlogy and
`Ohsletrics. In the press.
`
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`Pharmacosmos A/S v. American Regent, Inc.
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