MemorialHospital of South Bend 33

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December 2_. 2001

United States Nuclear Regulatory Commission Region III, \ flical Licensing Section 801 Warren, ".e Road Lisle, IL 605'432

RE: Misad&-. istration Report

Dear Sirs:

We have en. -sed the report on three (3) misadministrations which occurred due to a dose calibrator

calibration I-or at our radiopharmacy for a beta-emitting radiopharmaceutical, Sm-153 supplied by

them in unit _`osage form.

If you have _-y questions, please contact Dick Selle, the Nuclear Medicine Manager (219-284-3112),

Nina Johnsc -.. our RSO, or myself. Our consulting physicist who assisted with this report is Tracy King

of Medical Physics Consultants can be reached at 734-662-3197. Thank you for your cooperation with

this matter.

Sincerely,

Daif A

David A. H, .-nback, M.D.

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12 27 01 lit 11:24 I'AA , .540bZ 3/Z4

REPORT OF MISADMINISTRATION TO USNRC

Licensee's Name: Memorial Hospital South Bend Indiana

Prescribing Physician's Name: Dr. David A. Hornback

Brief Description of Event: Three patients were administered dosages of

Samarium-1 53 that were lower than the prescribed dosage by more than 20%.

Patient A. Date: Prescription No. Prescribed Activity: Administered Activity:

Patient B. Date: Prescription No. Prescribed Activity: Administered Activity:

Patient C. Date: Prescription No. Prescribed Activity: Administered Activity:

06/28/2000 718140 67 mCi Sm-153 49.86 mCi Sm-153

08/23/2000 735173 68 mCi Sm-153 48.44 mCi Sm-153

05/11/2001 816061 60 mCi Sm-1 53 45.59 mCi Sm-153

Why the Events Occurred: Unit patient dosages of Sm-153 were ordered from Spectrum Pharmacy, Mishawaka, IN, with a requested activity for a specified time. Spectrum Pharmacay filled these orders by withdrawing a calculated volume of Sm -153 into a 3 or 5 ml syringe from a 10 ml vial calibrated at 50 mCi/ml at noon on Wednesday. The syringes were assayed in a Capintec ionization chamber dose calibrator on a setting of 170, and the volume in the syringe was adjusted, if necessary, to produce an activity matching that requested by the ordering facility. The dose calibrator setting of 170 was determined on July 23, 1997, using a NIST traceable Sm-153 standard in a 10 ml vial. During the period December 12-20, 2001, Spectrum Pharmacy determined that the 170 dial setting was appropriate only for the 10 ml glass vial, not for a syringe. Using another NIST traceable Sm-153 standard, Spectrum Pharmacy determined that the actual activity in a syringe is 28.2% less than the activity measured on the 170 setting.

Effect on the Patients: The Sm-153 was administered for palliation of bone pain. The effect, if any, of under dosing by the 24.0% to 28.8% is not known- It

.III ý . 1 1-

12 27 01 lI. I I:24 FA.A 1J4bbZJ //4 . i

would presumably result in a more than expected number of patier':s not experiencing relief or experiencing less relief from their symptoms

Improvements Needed, and Actions Taken, to Prevent Recurrence: Spectrum Pharmacy, Mishawaka, has established that a Capintec cose calibrtor setting of 170 is appropriate for the 10 ml of Sm-153 received frorr *ne manufacturer. It has also been determined that a setting of 273 is aopropriate for Sm-153 in a 3 ml syringe. Both vial and syringe require no geome-, c correction factor over the range of 0.5 to 3 ml.

The Sm-1 53 dosages dispensed by Spectrum Pharmacy will be de:ermined by a subtraction technique:

a. assay 10 ml vial on 170 setting b. draw volume required into syringe, based on desired dosage and

concentration of the Sm-153 solution c. assay remainder in 10 ml vial on 170 setting d. record dosage in syringe by subtracting remainder assay from the

whole vial assay e. confirm dosage by assaying the syringe on the 273 se.!rng

Since Sm-153 is primarily a beta emitter, facilities receiving and administering the Sm-1 53 syringes as a unit dose should, in accordance with 10 CF, Part 35, record the administered dosage based on the activity specified by Mqe preparer, Spectrum Pharmacy. A mathematical decay correction should be zilized if the actual time of administration differs substantially from the time for '- 'hich the dosage has been prepared. Those facilities with Capintec dose ca orators could assay the syringe on the 273 setting to confirm the activity of Sm- 53 in the syringe, but the recorded administered dosage should be the (decay corrected) activity specified by Spectrum Pharmacy. If the facility assay differs from Spectrum's specified activity by more than 10%, the dosage shoul1 not be administered and Spectrum should be contacted to resolve the discrepancy.

All appropriate staff at Spectrum Pharmacy and the clinical facility 1ave been (will be) instructed regarding the above procedure.

Did Licensee Notify Patient or Guardian? Each surviving patiert has or will be notified.

Information Provided to Patient, if any: A copy of this report is being provided to each surviving patient.

Samarium-153 Quadramet Dosage Error Data: Date: 12-21-2001 Hospital Receiving Doses: Memorial Hospital South Bend, IN

Person Receiving Data: Dr. Nina Johnson\ Tracy King

Date of Prescription Act. Pres./ Syringe Co Prescription Number Dispensed Error As

6/28/'2000 718140 67/72.2 -28.2% 51.

8123,2 r� r� (�

5/111 12 l

tA£ / AO

S 16061 6n / #y�

- 9R7%0

-9 90/A

rrected say 84

49 54

49 59

Date of Injection

6/28/2000-r -r

8/23/2000

5/1 1/2001

r -ITime of Injection

16:36

11:30

10:00. --_, . 5/11/2001 . 2 8 2ý/.- 28.2%1 -28.2% ~

- 9R 90/A

- 98 90/

Administered Activity 49.86

48.44

45.59

4.2-8.2%1-

_____________ -i._9£9o')/.

-282% . -- 9R 2%.~

____1 _______ -282%-1- ')R 90%

____ -4~~- 2&2% - t -_ 95R 90/4

- 98 2%

-') 920/

-282%__4.4 -

I 82% -

282% . 1 --- 9R90%

_____________4-282%I

__________ 4. 4 -f -t -1---

I I_______________ J __________ I.

% Error

-2.5.6%

-28.8%

-24.0%. 000 68/69 . -282% 8/2' )/2000

"72 Z, ! '-/'2.

..... ... .------ --- -- --

SPECT UM PInc.

December 24, 200l NUCLEAR MEDICINE COLLEAGUES:

RE: ACCOUNT OF EVENTS LEADING TO CALIBRATION ERROR FOR Sm-153

The following is an explanation pertaining to the mistake made in the calibration and dispensing of prescriptions of Samarium-153 Quadramet. This error in calibration, by the pharmacy personnel, ultimately led to the apparent misadministrations within your hospital.

Samarium-153 Quadramet is an injectable radiopharmaceutical indicated for the palliative treatment of metastatic bone pain in terminal cancer patients. It is predominantly a Beta emitting isotope with some gamma emitting components.

Spectrum Pharmacy, Inc first began use of Smn-153 Quadramet on July 23, 1997. At this time a National Institute of Standards and Technology (NIST) traceable standard of Samarium-153 was obtained from DuPont Pharmaceuticals to facilitate calibration of Spectrumn Phannacy, Inc.'s Capintec dose calibrators. This NIST traceable vial was assayed in our dose calibrators to obtain a NIST traceable reference setting for dispensing Sm-153 Quadramet. A value of 170 was obtained and this value was used to calibrate all syringes containing Quadramet. On the morning of December 12, 2001 it came to the attention of one of the pharmacists that upon using a vial subtraction technique based on the manufacturer's assay, the assay of the vial and the assay of the syringe on the 170 calibration setting differed by a factor of approximately minus 25%. Spectrum Pharmacy, Inc. contacted both their health physics consultant, and the current manufacturer of Sm-153 Quadramet concerning this issue. The manufacturer (Berlex) stated that they did not believe that there was a significant difference in assays obtained whether the dose was in a vial or a plastic syringe. They also stated that there were no documented incidents of geometrical variation between syringes and vials for Sm-153. Our medical physics consultant believed that there may indeed be a difference in assays obtained between a glass vial and a plastic syringe due to the Beta emitting component of Samarium-153.

In order to determine the possible difference in assays, an NIST traceable standard was once again ordered from Bristol-Myer-Squibb Medical Imaging Division to obtain a syringe correction value. The Nuclear Regulatory Commission Region 3 office was notified of possible misadministrations of Sm-153 Quadramet doses on the morning of December 14, 2001. After reporting these possible incidents all hospitals involved were contacted by Spectrum Pharmacy, Inc. and instructed to ,c-ll t ,e Nuclear Regulatory Ce:uim I. Ion's Operations phone 1umber to report the possible misadministrations. One hospital w\hilcl received three doses in late 1998 was contacted on December 18Ith, 2001. The Nuclear Reg'ulatrV Commission issued a preliminary notification of the event on the morning of December 18. 2001. A copy was sent to SpectLrum Pharmacy, Inc. as well as to all hospitals which werc id•rti Fied as to have received S'; -13 QLiadramet doses fro ii Spectrum Pharmacy, Inc.

1301 Fý' cjrn Blvd., Suite 100 Mishao,. -q-a, IN 46544 (21?9) 5•-_072

Page 2 ot'2

On the afternoon of December 20, 2001 assays of the NIST traceable source were performed b\ Spectrum Pharmacy, Inc's Radiation Safety Officer, Scott Van Heesbeke R.Ph. The results of these assays were forwarded to Bob Anger our health physics consultant who was going to assist in the calculations for geometrical variation and differences of attenuation.

Upon evaluation of this data it was determined that there was indeed a difference in assays of Samarium- 153 due to the density of the IOml glass vial the product is calibrated and received from the manufacturer in, and the density of a plastic 3ml or 5ml Becton-Dickinson syringe which the Quadramet was assayed and dispensed for injection in. It was this attenuation difference that resulted in the calibration error due to using a syringe to dispense the Samarium153 Quadramet. The data obtained from this calibration was used to obtain a secondary NIST traceable syringe dose calibrator reference setting of 273. From this point on Spectrum Pharmacy, Inc. has developed a protocol for assaying Sm-153 Quadramet patient injections which uses a manufacturer's assay vial subtraction technique and a secondary check of the assa\ using the 273 dose calibrator syringe reference setting.

Thank you for your time and assistance in resolving this matter.

Sincerely,

Scott Van Heesbeke R.Ph. Manager.RSO Spectrum Pharmacy, Inc.

SPEPT UM PHA RACY Inc.

\'R' ACTION P11,\N F()R 1',I' I)TIN( PL_.Pt . DATI December 24, 2-)()1

Dear Spectrum Pharmacy Colleagues:

On the afternoon of December 14, 2001 i, Scott Vanileý. -- l ke of Spectrum Pharmacy spoke with the radiation safety officer of your hospital. -orined this individual that the possibility existed that prescriptions of Samariu'-i53 K.-Jramet were calibrated with 20% to 309o less activity than the amount indicated on i-. ?rescription and ordered by the physician. This error occurred due to a difference ir assay characteristics between a l0mI glass vial and a 3ml or 5mnl plastic syringe. Thi .. s an unintentional mistake and we are very sorry that this error has occurred.

Please be aware that we are working with the Nuclear RzViatory Commission and our health physics consultant to make the reporting of these - .dents, by your hospital, go as easily and accurately as possible. Attached you will fin. 2ata specific to your hospital indicating the prescriptions dispensed, the date dispens,: -.nd the suspected dosage error as calculated by our health physics consultant. There is c. an article from the Journal of Nuclear Medicine relating to the management of bonz -.-:in.

You are required to report to the Nuclear Regulatory Cc7 rzission, in writing, within 15 days of initially discovering a misadministration (Decen-_ :- 29, 200 1). When corresponding with the Nuclear Regulatory Commissior.. ,ncerning this incident, you may consult the infonlnation included with this letter. T.. :nfon-nation lists the pertinent data you will need in putting together your report.

Additionally, our health physics consultant has prepared ý:-ne guidelines that can be modified by each facility to prepare your written report i.: i.e NRC. In particular, the authorized users may want to expand the information in :i effect on the patient section.

SUGGESTIONS FOR TIlE WRITTEN REPORT 10 THE NRC

Brief description of the event:

Patients were administered an amount of Sin-153 that di::l ed from the prescribed amount by more than 20%. (List each patient ID, not the ::ient's name, the ordered and the actual adm inir ,red activities, as obtained Ir'm the V ._rn-macy)

1301 Milburn Blvd., Suite 100 Mishawaka, IN 46544 (2191 255-5072

IaLC -1 o1 "I

Wh\ it occurred

Unit patient dosa.'e_ ol'Sm-! 153 were ordered from Spectrum Pharmacy, Misha\waka, IN, with a requested altvity for a specified time. Spectrum Pharmacy filled these orders by withdrawing a ca.",lated Volunme of Sm-153 into a 3 or 5 ml syringe from a 10 ml \ial calibrated at 50n ml at noon on Wednesday. The syringes were assayed in a Capintec ionizati.,:- chamber dose calibrator on a setting of 170 , and the volume of the syringe was adlu>J, if necessary, to produce an activity matching that requested by the ordering facilit\ -he dose calibrator setting of 170 was determined on July 23, 1997, using a NIST trac--able Sm-153 standard in a lOml vial. During the period December 1220, 2001, Spectru:' Pharmacy determined that the 170 dial setting was appropriate only for the 10 ml glass ' ial, not for a syringe. Using another NIST traceable Sm-153 standard, Spectru:--. Pharmacy determined that the actual activity in a syringe is 28.2% less than the acti\ ::\ measured on the 170 setting.

Effect on the paHtt(s);

The Sm-153 wa>s Jministered for palliation of bone pain. The effect, if any, of underdosing by 2_ to 299% would presumably be a more than expected number of patients not experiencing relief from their symptoms.

Improvements needed, and actions taken, to prevent recurrence:

Spectrum Pharma: ,, Mishawaka, has established that a Capintec dose calibrator setting of 170 is appropr.lte for the 10 ml of Smn-I 53 received from the manufacturer. It has also been determined :eat a setting of 273 is appropriate for Sm-153 in a 3 ml syringe. Both vial and syringe reqire no geometric correction factor over the range of 0.5 to 3 ml.

The Sm-153 dosages dispensed by Spectrum Pharmacy will be determined by a subtraction techna ue:

a. ass , 10 ml vial on 170 setting b. drav. volume required into syringe, based on desired dosage and

corncentration of the Sm-153 solution c. assay remainder in 10 ml vial on 170 setting d. record dosage in syringe by subtracting remainder assay from the whole

Via! assay e. confirm dosage by assaying the syringe on 273 setting

Page oi I

Since Sm- 153 is primarily a beta emitter, Facilities recei\,ing and administering the Sm153 syringes as a unit dose should, in accordance with 10 CFR Part 35, record the administered dosage based on the activity specified by the preparer, Spectrum Pharmacy. A mathematical decay correction should be utilized if the actual time of administration differs substantially from the time for which the dosage has been prepared. Those facilities with Capintec dose calibrators could assay the syringe on the 273 setting to confirm the activity of Sm-153 in the syringe, but the recorded administered dosage should be the (decay corrected) activity specified by Spectrum Pharmacy. Ifthe facility assay differs from Spectrumn'S specified activity by more than 10%, the dosage should not be administered and Spectrum should be contacted to resolve the discrepancy.

All appropriate staff at Spectrum Pharmacy and the clinical facility have been (will be) instructed regarding the above procedures.

Were the patients notified? (If not, why not?)

This needs to be addressed for each of the patients identified in the "Brief description of the event".

I hope the information above and the provided enclosed data helps streamline and simplify your process and effort in the matter. Again, I am very sorry for the error in the calibration of the Sm-153 and promise you that corrective actions have already been implemented.

Sincerely,

Scott Van Heesbeke R.Ph. Manager/RSO Spectrum Pharmacy, Inc.

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ACKNOWLEDGMENTS

I LI:dI lit l iliIEcc I

N ICLsii BIL lpt aLiiwi( IL,' C it

REFERENCES

dIml All ,I iý 'I ) ilI )N I['-

II II

'Ii

ii

'I,:

:11 . I' lii

I' .1.1 ii. lli� I

At . ilIw'

J' tii a v i t~ I s

N[0c11 tlt ii''

n 1-11,''1

I' I '' b I

H. , ilA ; t i i 1.. 1 '1 I 3 ý ' ,0 1 1 lý IlI l' n

I 11, ' 1 w It I I, Ii I P 'I vt R'' 11.I I ', or

I t 1 1" SC I ;11 11,od I bt1 ofl I 'Il t ll

II I dn, 111k "1j 1 1 P " B,- i 1'' \l!'l Cut '1)11111' I tl ,

I k~ I J I I' I il I lil t i c s' I i t I g I q L te I t a U ' . 'itt>o

ICM -t Y 98 93 0

PII, , I L t"I 1 II'. 'll id \% t, ll)m 'cuNi l v Iv i'S [Sr. ll'1in i

iutl I I Ph, KJI II It h"plltalIIII1cujl j aron L~t Itl i cIlimclt''iL1 cx tii

itt I! '1''.11 LI ld , T.\, Fi V. Rli, Cnip DA', MilrIntll Rl 'I .Al

dwn n I i , ii-tininutll cin v ol1

ithI detection a11d iloclizat' ion of bunl

I -1Il 11 III a l lo vclIL'ni aIIn Mlt e buo1

scanrIl'TIt' \-,, ; M I',

Itn i), 'If Nit II'o Iý Ptiol :il C, i',lal otl~tl \Ii, Be illinl Ni '

)iI' I "'vSr tlil IlIIIIUlIinig uIina ii di' gl ii va 1 11 i

in'"',' I 1,1 ; l, I l)t.'1 . o I iii,4

,I N11i Ii, " r S I t il Iktlt) I Sjli H ,ti)'

�1

cl, 1) (11 1 ,111. )()1 1-,. .1 11 ,

'1

QUADRAMET' (Samnariumn Sm 153 Lexidronamn Inijection)

'R RIPTION:

AB I .100Fc -f3i

.1222, 'SW2 ' .2,.221 1.2 ! ' I ' 2

22 '

II.

TABLE 1 PRINCIPAL RADI

I ,Iernal Radiatioif: 2k j2 ::2.

.,03 .2121221 21 l: 2(.2

'active ldjwy3' 'minI 2 2l 1, ( : C1.f,ý6 V

12.0211InTbli1. ,'e Alia i .2 .2;vl 1, '

TABLE 2 PHYSICAL DECAY CH

0. Time

(hour)' Factor

360 II

-200 2222,

_160

It

CLINICAL PHARMACOLOGY: "[' it' 1[ :v f2. ,['' .

Dist ibut i o

Sku I U Ii Uptake:

NIe tn a b01ilis :

Elimination: .

*1. 2 .1 I I . ' h

I .l. 2. 2 2" F

:I 'if l, 12 2 J, !J .t

iii 2,1 :1

122.~ 1 ~ .. Gender Differences: lic it

2. ~~:OA J, . , '22 Special Populations

J10 0 "0l i1:,j 'ý, ir j, 1 ý::j:

SAMaARIUNIoI153 J11 I 212 , 22

ATION EM'1ISSION DATA .,21d 1 _.jf

Radiation .,1.' :j.' Energy Drug/Dlrug Inlteractionh (keV)y Abundanice2.J .2 ' , 'I 1

01~, Pliarinacodyilarnics

.2.~~~~ 2' ''6, I ' 2032 .

J t1 ' 1,2 ll , li ' '21 '21121'.

CLINICAL TRIALS

SAMARIUM-153 '' (2 '2..I' n 11 '. 0

ART, HALF-LIFE 46.3 HOURS'1'' . 1 2..22 .2.1 '02

.93 DAYS) Tinme 1'23 '' I2'o.

-hur ~ Factor- ul (:. 2. )2 I I in

Y)2.) I2, .2 2 .21I o 0

'''2t )Jl fl

, 1.1: 2 il ,, '2 '' fij! '122' 2~l~ l2 .2 i 1: 2

22'''~ ~ J:. 211 211' 12111

2 0' 1.22 . 2 , 222, i II: 22. ' l' d 2) ill,

2:' ~ ~ ~ ~ ý IMo2I~I.2

'2 2 ' '2 1 2: 123 ''pi,2

I 2, II: '1,1 . 2. 12, 11 ! i " I 22

d 1.* 1

7

I i '. ; !j

j1 ,2 li . I ý

lc , I ,i 2(2 .0 Wf i i

l202 0'dfI ifIf d,, If 1: ),

tf, 61' 11tff.c3

It212ll 1.2.1 22il '2 2,il .2 ''27ý

nil ~ ~ ýil 1,I2u (21.20 0 1112

1.0.. 3 n '. .11 2 'l s2',n2

,:sec ofnu '20 "1",O j2 2..22 .2 ,

2'~jllj 1 01[1D ý readi l cfidil..221.n lIr

V h"s'i l !lie 2223:20 J , 211ý lw.In2.

on J2 2~,' ill a 2,0 1ý2 2 i 1 .07

10 2Vl .Jdi lf

[1ii, , 1. 2.22222,0 12w 20(221 ,,i-e 1 2

.1t j , , fl <C 11122 2a Iim 02 (oo l d1.220 2 c f2fln 1 I. -0 IJ

]2,22 f; 2 2 ,3 2'i22n 232... !2k' if' A,

;;U2.311.. i:j I 211 il.( 2222ix ' 2 , .(n , 1

.322.. j:y OF' 11 1~C

TabIt 3: COMPARISON OF WEEKLY PAIN SCORES (cjj AFTE13 QUADRAMET 1 OmCrky or PLACEBO IV [Intent to Treatj

PHECAUTIONS:

wl,!i 1 :I 1 16

t 1

l y J

1 j

"A:.: a:,

"r ýVt

w

:f. ilý. I J

Qu I

111:Zu

:1 ; , !ý.l 1 1 .. ! - .ý

.ýA J 1

A .11 I I ý ijý, J ! k)ýý I JI :1 !.1:,

jlh,;

I I I I , t i

1 j j

If! li.x -ýi!Ljim ul ;fit

- iw ý'-Cical

i.-i 7,,

I It jiia e'XI:e

I the paliHill

-ýIdlts 10 Iflip

-.Ient ufifiýýy

!;ýSl 6 ricul"i

-ý[ lcý sewid

J10 oe flushed S snould vfash

JýS NO L&;3!

feeks niief ,,eeKS, U Linli

ts had at least Limarium- 153

'equale maff-',?,

hurifars gmý

-cgenlicily slbjy r1g!kg/diLy ýJ on day ý'19 ji 3 1330 1 of !Judml dose) ,[ýilstrdhy S-g-

bv ciýý ý;ulýý;il.ý-j

tj i cuf& Otte Use J -1:

lllLý IT :ýf :Ij *,t,, A ,Jý k a, 11, L-1 iII: ý , ý 1: 3 J r e c. I If I a 2 ý S L 11 11,ý I I

I G I I [d I J 11) 1 t I

P; I ly Jli: A! r U ýJq 1 11 u L f'- h uý ou-ilil" 1-ui

A.ý, 1 :1 :!,:LTl u;l 'till Ll,: it -1tJf!'M c[ v6lri fer,31

INFORMATION FOR PATIENTS ShsLllJ 1101,;ý l"'illij ti'ailil, ý11ý1111 i At I"ll Is, I I!, "O uted W"'it se I f otllrlýý lft lhti f;k:.11tu;,6its ii be 101 12 holl tfw iblt, a lý,du[ Aii2ýji, Lý useo, ialn, Lifilia:, 111.0 'ýýIe 1ý, 7

jll(:f ýljl.,IcJ J; I:, <ýiould L't, li'l-11'ed q Ih,;l11!;.);1iý 1; !ik,ýjd IJ It: dtlS Wilo LlJ:t 19 ihC ýý,llhiig l7

if it, i 'ýI V074-, I') Lill, luf I - ::, Lit 14 c;m

:;,!,I 17!1,ý JlUtaSI 1;i Illy allCý 1. ;,I- 1-111ý ;il"i" dIL'i if,11ý l! I mWIft liiýtcllllf! S,-*

v h 1',-t !"I ill PJ!- iIý ij ii-.Iký I"tijill 1, J!Ce 1ý,t j,

Jil Jjlf, ý1! nt.- J 1ý

LABORATORY TESTS cIJf!IIl11'11I,:[liIif o:jjJ ý,1101,ld I;t 'I JIU 1.1L, lo; A

Ljjp iiii, f"N ju-11 Ill

Ill i 1 1 31 lmk iItýý 1.,:il i-IJI; , dli:,ý , ;if 1;1ý iill-fe.! lw q the ;Ifs: pa!ýIenl it ('11ciffIl 2i':,li"L vins U 1 diariJ:cd HIý'll"'.v , 10 ý.3ý-.

IMi fvliý no;iffal t' If :,, 8 23) The exteli! [j : .1, riýj[ ýi;Ijm , 'I.,ilion sw ,,ld bt 'i'lcý-:"

it 4'Ll:u DRUG INTERACTIONS Till, r.l3tt& loxiCtly ýl 0:11ý3-ý

ýt Ill It'v il ljdldiýýIl llýis fi-; ljttý'l '311ýdied 0-iý-amci sn uld in.ct tu'; Chf,,7ýý :f.lP*y X UA;t::r4il beýlllý ;nciljlli-il :!Iulapy 1jile , the btreid OuN,12!ý11ýý sho'. ý! boý givef ý14 ý tithe't J !feýlmltfllý l1as been fecii),ý- ist", S"l-'a in) CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Cliiý-cgý,: , 1)] if Qudf;jflw1 is l!"'i llktdy f:( 2-yn f 0i t i-ý k ýt. fI:lzI!ldf Lif, to llý 11131t F,ýý Ill ;I ::.[! Výt) fiý[ýiliejýtjýj Ilhý; do,,alj- to 333 r:,; lint ill j clifo.11c oielaf,ý

- , ýnol Ifit lia) li" e's 16 lijlý ýcrlý idilýý lu'llIll illf%!l r! i,.Il 3.11 ".,i;s diýt ;,s

ýJll rfi;lf-ýl I,:: thAlk 'All]', A' f, 'alc 10iilas

if I.t , jr. I J, 'j" :,' ill `Alii I, 0 ý,l , .,) I

cl.: L A ILI! J1 tlidi, lici ýI) IL: 4

if Pwd I.. If 1 71.:

Table 4: COMPARISON OF WEEKLY MEAN ANALGESIC USE (a) BETWEEN I QUADRAMET 1.0 mCi/kg AND PLACEBO GROUPS jIntent to Treat]

1---- 1, -- - - -- -- - -- -- -- - - - -- - -- - ----- - -- . 'Sl B I

"N'IFFF, 0 llýý i!ý Mhi ýtjo .1 11 ill trtj

W )c 8") 125 i 7l 2

2 1 Z,, 1 038 41 1414 3- (276 7 3 1 1 3'ý, 9 rd G 1 1 - 6 d 2

4 1_ -- __ 1 '4 0' 1

ialý e3:,-. iý ijld c' ý,j- tmU f! :1 f;i)l1c. rD) E:I Vi!ll i Ill 1,::17,; 1:ý

u 5 ;li-'l tý j t 11cl!" -,d i K i ulý di-Iliq 'I: )Iil;ýJj ill ill JJ-li L-[,:.

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Table 5: NUMBER AND PERCENT OF PATIENTS WHO EXPERIENCED MARROW TOXICITY IN CLINICAL TRIALS OF QUADRAMET

Tuiuty Plau!ýo 10 pld:-,:ýbo 10 llC'i41tIfj I'loIL f;tý') 1 1" i I I G L adil, 1,ý 85 N H-8'5- I I -- I ý0) cl - -ý ý I - ý31,ý - -02 85 000"1') 161 Kil',L) ill Will) I Iftl "L, I 3 ""0 0 0 0

1 3 0 (0111") 0 (01%) 0 2 1

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