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POINTS FROM
LECTURES BY
CLEVELAND CLINIC
AND VI SI TI NG
FACULTY
MEDICAL GRAND ROUNDS WILLIAM 5.
iU j n
1
j j j i >1 J ^mwm
Andropause, testosterone therapy,
and quality of life in aging men
Hypogonadism
may affect
5 million men
in the US
JOHN E. MORLEY, MB, BCH*
D i r e c t o r , D i v i s i o n o f G e r i a t r i c M e d i c i n e , S t . L o u i s U n i v e r s i t y H e a l t h S c i e n c e s
C e n t e r , M i s s o u r i ; G e r i a t r i c R e s e a r c h , E d u c a t i o n , a n d C l i n i c a l C e n t e r , S t .
L o u i s V e t e r a n s A d m i n i s t r a t i o n M e d i c a l C e n t e r
ABSTRACT
Testosterone therapy can improve quality
of life in aging men because aging is
accompanied by declining testosterone
levels that may contribute to decreases in
muscle mass, bone density, libido,
stamina, and cognition. Hypogonadal
men can be identified by a test for
bioavailable testosterone or by a free
testosterone assay that uses dialysis or
ultracentrifugation methods.
".. .The sixth age shifts
Into the lean and slippered pantaloon
With spectacles on nose and pouch on side;
His youthful hose, well saved, a world too wide
For his shrunk shank, and his big manly voice,
Turning again toward childish treble, pipes
And whistles in his sound..."
(William Shakespeare, As You Like It)
F T H E SE SYMPTOMSmuscl e wasting,
regression of secondary sexual charac-
teristics, a rising voice pitchwere to develop
in a young man, we would have no difficulty
in diagnosing hypogonadism. These symp-
toms may signal hypogonadism in aging men
as well.
' T h e a u t h o r h a s i n d i c a t e d t h a t h e h a s r e l a t i o n s h i p s w h i c h , i n t h e c o n t e x t o f
h i s p r e s e n t a t i o n , c o u l d b e p e r c e i v e d a s p o t e n t i a l c o n f l i c t o f i n t e r e s t . H e h a s
r e c e i v e d g r a n t s o r r e s e a r c h s u p p o r t f r o m M e r c k , N e s t e c , B a y e r , a n d B .
B r a u n M c G a w , a n d h a s s e r v e d o n t h e s p e a k e r ' s b u r e a u f o r L X N , O r g a n o n ,
G e r i M e d o f A m e r i c a , U n i M e d , E s s e n t i a , A l z a , P h a r m a c i a & U p j o h n , G l a x o
W e l l c o m e , B . B r a u n M c G a w , B r i s t o l - M y e r s S q u i b b , H o e c h s t M a r i o n R o u s s e l ,
M e r c k , N o v a r t i s , P a r k e - D a v i s , S m i t h k l i n e B e e c h a m , a n d P fi z e r .
The common wisdom that men do not
undergo menopause is being replaced: many
aging menperhaps 5 million in the United
Statesdo experience androgen deficiencies
that impair quality of life. For these men,
testosterone replacement therapy may
improve libido, muscle mass, bone mass, cog-
nition, and energy levels.
NATURAL HISTORY OF TESTOSTERONE
After age 30, levels of total and bioavailable
testosterone in men decrease by 1% to 2%
per year.
1
Thi s decrease may be caused in
part by decreased testosterone production
and in part by slowly rising levels of sex hor-
mone-binding globulin, the protein that
binds testosterone and removes it from circu-
lation. Levels of luteinizing hormone, which
also affects testosterone bioavailability, do
not rise until age 85 to 95.
These subtle changes may be easy to over-
look because they develop over a longer peri-
od of time than the changes associated with
female menopause.
I DENTI FYI NG TESTOSTERONE DEFI CI ENCY
"Andropause" can be defined as a complex of
androgen-related symptoms that occur in the
presence of low levels of testosterone.2
Symptoms include:
Decreased muscle mass or strength
Cognitive changes
Increased fat mass, particularly visceral fat
Osteoporosis
Low sense of well-being
Decreased sexual desire and impaired sex-
ual function
Mood changes, including depression, irri-
tability, loss of motivation, and lethargy
8 8 0 CLEVELAND CLINIC JOURNAL OF MEDI CI NE VOLUME 67 NUMBER 1 2 DECEMBER 2000
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WelChol (colesevelam HCI) did not induce any clinically significant reduction in the absorption of vitamins A, D, E, or K during clinical trials
of up to 1 year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat soluble vitamin deficiencies.
WelChol is classified as Pregnancy Category B.
As with ail cholesterol-lowering agents, serum total-C, LDL-C, and TG levels should be determined periodically based on NCEP guidelines to
confirm favorable initial and long-term responses.
R e fe r e n c e s : 1 . A m e r i c a n H e a r t A s s o c i a t i o n C h o l e s t e r o l S t a t i s t i c s . A v a i l a b l e a t : h t t p : / / v w w v . a m e r i c a n h e a r t . o r g / c h o l e s t e r o l / p h y s _ s t a t s . h t m . A c c e s s e d J u n e 7 , 2 0 0 0 . 2 . P e a r s o n T A , L a u r o r a I , C h u H , K a fo n e k S .
T h e l i p i d t r e a t m e n t a s s e s s m e n t p r o j e c t ( L - T A P ) . Arch Intern Med. 2 0 0 0 : 1 6 0 : 4 5 9 - 4 6 7 . 3 . Physicians'Desk Reference54th e d . M o n t v a l e , N J : M e d i c a l E c o n o m i c s C o ; 2 0 0 0 : 2 2 5 4 - 2 2 5 7 ( a t o r v a s t a t i n ) .
4 . Physicians' Desk Reference". 5 4 t h e d . M o n t v a l e , N J : M e d i c a l E c o n o m i c s C o ; 2 0 0 0 : 1 9 1 7 - 1 9 2 0 ( s i m v a s t a t i n ) .
W E L C H O L (colesevelam hydrochloride) TABLETS
Rx onl y
B rief S u mma rys e e p a c k a g e ins ert fo r full p re s c rib in g info rma tio n.
I NDI CATI ONS A N D USAGE
W e lC h o l, a d min is te re d a lo n e o r in c o mb i n a ti o n w i th a n H M G - C o A re d u c ta s e
inhibito r, is in d ic a te d a s a d ju n c tive th e ra p y to die t a n d e xe rc is e fo r th e re d u c -
tio n o f e le va te d L D L c h o le s te ro l in p a tie n ts w i th p rima ry h yp e rc h o le s te ro le mia
(Fre dric ks o n T ype lla).
CONT RAI NDI CAT I ONS
W e lC h o l is c o n tra in d ic a te d in individua ls w i th b o w e l o b s tru c ti o n a n d in individ-
ua ls w h o ha ve s h o w n hype rs e ns itivity to a ny o f th e c o mp o n e n ts o f W e lC ho l.
PRECAUT I ONS
Gener al : P a tie nts w i th T G levels gre a te r th a n 3 0 0 m g / d L w e re e xc l u d e d fro m
W e lC h o l c linic a l tria ls . C a u tio n s h o u ld b e e xe rc is e d w h e n tre a ting p a tie n ts w i th
T G le ve ls gre a te r th a n 3 0 0 m g / d L .
In no n- c linic a l s afety s tudie s , ra ts a dminis te re d w ith c o le s e ve la m a t d o s e s gre a te r
th a n 3 0 - fo l d th e p ro je c te d h u ma n clinical d o s e e xpe rie n c e d he mo rrha ge fro m vit-
a min K deficiency. W e lC h o l d id no t in d u c e any clinically s ignific a nt re duc tio n in
th e a b s o rp tio n o f vita mins A , D , E , o r K d u rin g c linic a l trials of u p to o n e year.
H o we ve r, c a u tio n s h o u ld b e e xe rc is e d w h e n tre a ting pa tie nts w i th a s us c e ptibil-
ity to vita min K o r fat s o luble vita min de fic ie nc ie s .
T h e s a fe ty a n d e ffic a c y o f W e lC h o l in p a tie n ts w i th d ys p h a g ia , s w a llo w in g d is -
o rd e rs , s e ve re g a s tro in te s tin a l mo tility d is o rd e rs , o r ma jo r g a s tro in te s tin a l tra c t
s u rg e ry ha ve n o t b e e n e s ta b lis h e d . C o n s e q u e n tly, c a u ti o n s h o u l d b e e xe r-
c i s e d w h e n W e lC h o l is u s e d in p a tie n ts w i th th e s e g a s tro in te s tin a l d is o rd e rs .
I nf or mat i on for t he Pat i ent : W e lC h o l ma y b e ta k e n o n c e p e r d a y w i th a me a l,
o r ta k e n tw ic e pe r d a y in d ivid e d d o s e s w i th me a ls . P a tie nts s h o u l d b e d ire c t-
e d to ta k e W e lC h o l w i th a liquid a n d a me a l, a n d a d h e re to the ir N C E P - re c -
o m m e n d e d die t. P a tie nts s h o u ld tell the ir p h ys ic ia n s if th e y are p re g n a n t, a re
in te n d in g to b e c o me p re g n a n t, o r a re b re a s t- fe e d in g .
Labor at or y Tests: S e ru m to ta l - C , L D L - C , a n d T G levels s h o u ld b e d e te rmin e d
pe rio dic a lly b a s e d o n N C E P guide line s to c o n firm fa vo ra ble initial a n d a d e -
q u a te l o n g - te rm re s p o n s e s .
Dr ug I nt eract i ons: W e lC h o l ha s be e n s tu d ie d in s e ve ra l h u ma n d ru g in te ra c -
tio n s tu d ie s in w h i c h it w a s a d min is te re d w i th a me a l a n d th e te s t d ru g .
W e lC h o l w a s fo u n d to ha ve n o s ignific a nt e ffe c t o n th e bio a va ila bility o f d i g o x-
in, lo va s ta tin, me to p ro lo l, quinidine , va lpro ic a c id , a n d wa rfa rin. W e lC h o l
d e c re a s e d th e Cmax a n d A U C o f s us ta ine d- re le a s e ve ra pa mil b y a p p ro xima te -
ly 31 % a n d 1 1 %, re s pe c tive ly. S inc e the re is a high d e g re e of va ria bility in th e
bio a va ila bility o f ve ra pa mil, th e c linic a l s ign ific a n c e o f th is fin d in g is unc le a r. In
c linic a l s tu d ie s , c o - a d min is tra tio n o f W e lC h o l w i th a to rva s ta tin , lo va s ta tin, o r
s imva s ta tin d id n o t inte rfe re w i th th e lip id - lo w e rin g a c tivity o f th e H M G - C o A
re d u c ta s e inhibito r. O th e r d ru g s ha ve no t b e e n s tu d ie d . W h e n a d min is te rin g
o th e r d r u g s fo r w h i c h a lte ra tio n s in b l o o d levels c o u l d ha ve a c linic a lly s ignifi-
c a n t e ffe c t o n s a fe ty o r e ffic a c y, phys ic ia ns s h o u ld c o n s id e r mo n ito rin g d r u g
levels o r e ffe c ts .
Car ci nogenesi s, Mut agenesi s, I mpai r ment of Ferti l i ty
A 1 0 4 - w e e k c a rc ino ge nic ity s tu d y w i th c o le s e ve la m (W elC hol) w a s c o n d u c te d
in C D - 1 mic e , a t o ra l die ta ry d o s e s u p to 3 g /k g /d a y. T his d o s e w a s a p p ro xi-
ma te ly 5 0 ti me s th e m a x i m u m r e c o m m e n d e d h u ma n d o s e o f
4 . 5 g /d a y, b a s e d o n b o d y w e ig h t, mg / k g . T he re w e re n o s ignific a nt d ru g -
i n d u c e d tu mo r findings in ma le o r fe ma le mic e . In a 1 04- w e e k c a rc in o g e n ic ity
s tu d y w i th c o le s e ve la m (W elC hol) in H a rla n S p ra g u e - D a w le y ra ts , a s ta tis tic a lly
s ignific a nt inc re a s e in th e inc ide nc e o f pa nc re a tic a c ina r cell a d e n o ma w a s s e e n
in ma le ra ts a t d o s e s >1 . 2 g / k g / d a y (a ppro xima te ly 2 0 time s th e ma xi mu m
h u ma n d o s e , b a s e d o n b o d y w e ig h t, mg /kg ) (trend te s t only). A s ta tis tic a lly s ig-
nific a nt inc re a s e in thyro id C - c e ll a d e n o ma w a s s e e n in fe ma le ra ts at 2. 4
g / k g / d a y (a ppro xima te ly 4 0 time s th e ma ximu m h u ma n d o s e , b a s e d o n b o d y
w e ig h t, mg /kg ).
C o le s e ve la m a n d fo u r d e g ra d a n ts pre s e nt in th e d r u g s u b s ta n c e ha ve b e e n
e va lu a te d fo r mu ta g e n ic ity in th e A me s te s t a n d a ma mma lia n c h r o mo s o ma l
a b e rra tio n te s t. T h e fo u r d e g ra d a n ts a n d a n e xtra c t o f th e pa re nt c o m p o u n d
d i d n o t e xhibit ge ne tic to xic ity in a n in vitro b a c te ria l mu ta g e n e s is a s s a y in
S . typhimurium a n d coli (A me s as s ay) w i th o r w i th o u t rat liver me ta b o lic a c ti-
va tio n. A n e xtra c t of th e pa re nt c o m p o u n d w a s po s itive in th e C h in e s e
H a ms te r O va ry (C H O ) cell c h ro mo s o ma l a b e rra tio n a s s a y in th e p re s e n c e o f
me ta b o lic a c tiva tio n a n d ne ga tive in th e a b s e n c e o f me ta b o lic a c tiva tio n . T h e
re s ults o f th e C H O c e ll c h ro mo s o ma l a b e rra tio n a s s a y w i th tw o o f th e fo u r
d e g ra d a n ts , d e c yla min e H C I a n d a mino he xyltrime thyl a mmo n i u m c h lo rid e H C I ,
w e re e q u ivo c a l in th e a b s e n c e o f me ta b o lic a c tiva tio n a n d ne ga tive in th e p re s -
e n c e o f me ta b o lic a c tiva tio n . T h e o th e r tw o d e g ra d a n ts , d id e c yla min e H C I a n d
6- d e c yla min o - h e xyltrime th yl a mmo n i u m c h lo rid e H C I , w e re ne ga tive in th e
p re s e n c e a n d a b s e n c e o f me ta b o lic a c tiva tio n.
C o le s e ve la m d id n o t impa ir fertility in ra ts a t d o s e s o f u p to 3 g / k g / d a y (a p p ro x-
ima te ly 5 0 time s th e ma xi mu m h u ma n d o s e , b a s e d o n b o d y w e ig h t, mg /k g ) .
P RE GNANCY
Pr egnancy Cat egor y B: R e p ro d u c tio n s tu d ie s h a ve b e e n p e rfo rme d in ra ts
a n d ra b b its a t d o s e s u p to 3 g / k g / d a y a n d 1 g / k g / d a y , re s pe c tive ly (a ppro xi-
ma te ly 5 0 a n d 17 time s th e ma xi mu m h u ma n d o s e , b a s e d o n b o d y w e ig h t,
mg /k g ) , a n d h a ve re ve a le d n o e vid e n c e o f h a rm to th e fe tu s d u e to c o le s e ve -
la m. T he re a re, ho we ve r, n o a d e q u a te a n d w e ll- c o n tro lle d s tu d ie s in p re g n a n t
w o me n . B e c a u s e a nima l re p ro d u c tio n s tu d ie s a re no t a lw a ys p re d ic tive of
h u ma n re s p o n s e , th is d ru g s h o u ld b e u s e d d u rin g p re g n a n c y o nly if c le a rly
n e e d e d . R e q u ire me n ts fo r vita min s a n d o th e r n u trie n ts a re in c re a s e d in pre g-
na nc y. T h e e ffe c t o f W e lC h o l o n th e a b s o rp tio n o f vita min s h a s n o t b e e n s tu d -
ie d in p re g n a n t w o m e n .
Pedi at r i c Use: T h e s a fe ty a n d e ffic a c y o f c o le s e ve la m (W elC hol) h a ve no t
b e e n e s ta b lis h e d in p e d ia tric p a tie n ts .
Geri at ri c Use: T h e re is n o e vid e n c e fo r s p e c ia l c o n s id e ra tio n s w h e n c o le -
s e ve la m (W elC hol) is a d min is te re d to e lde rly p a tie n ts .
ADVERSE REACT I ONS
W e l C h o l tr e a tm e n t- e m e r g e n t a d ve rs e e v e n ts th a t o c c u r r e d in g re a te r
th a n 2 % o f p a tie n ts in a n in te g ra te d s a fe ty a na lys is a re p re s e n te d in th e ta b le
b e lo w .
Fr equent ( > 2 %) Tr e a t me nt - Eme r ge nt Adv e r s e Event s By Tr eat ment
Ca t e gor y
B OD Y S Y S T E M / Pl a c e bo W E L C H O L ONLY
ADVERSE EVENT ( N=258) ( N=807)
% %
Body as a Wh o l e
I n fe c tio n 1 3 1 0
H e a d a c h e 8 6
P a in 7 5
B a c k P a in 6 3
A b d o mi n a l P a in 5 5
Flu S y n d ro me 3 3
A c c i d e n ta l I njury 3 4
A s th e n ia 2 4
Di gest i ve Sy s t e m
Fla tule nc e 14 12
C o n s ti p a ti o n 7 11
D ia rrhe a 7 5
N a u s e a 4 4
D ys p e p s i a 3 8
Respi r at or y Sy s t e m
S inus itis 4 2
R hinitis 3 3
C o u g h I n c re a s e d 2 2
P h a ryn g itis 2 3
Muscul oskel et al Syst em
M ya lg ia 0 2
OV E RDOS AGE
B e c a u s e W e lC h o l is n o t a b s o rb e d , th e ris k o f s ys te mic to xic ity is lo w. D o s e s in
e xc e s s o f 4 . 5 g p e r d a y ha ve no t b e e n te s te d .
DOSAGE A N D ADMI NI ST RAT I ON
Monot her apy: T h e r e c o mme n d e d s ta rtin g d o s e o f W e lC h o l is 3 ta b le ts ta k e n
tw i c e pe r d a y w i th me a ls o r 6 ta b le ts o n c e p e r d a y w i th a me a l. T h e W e lC h o l
d o s e c a n b e in c re a s e d to 7 ta b le ts , d e p e n d i n g u p o n th e d e s ire d th e ra p e u tic
e ffe c t. W e lC h o l s h o u l d b e ta k e n w i th a liquid.
Combi nat i on Ther apy: W e lC h o l, a t d o s e s of 4 to 6 ta b le ts p e r day, h a s b e e n
s h o w n to b e s a fe a n d e ffe c tive w h e n d o s e d a t th e s a me ti me (i.e., c o - a d mi n -
is tered) a s a n H M G - C o A re d u c ta s e inhibito r o r w h e n th e tw o d ru g s a re d o s e d
a p a rt. W e lC ho l s h o u l d be ta k e n w i th a liquid. Fo r ma xima l th e ra p e u tic e ffe c t in
c o mb i n a ti o n w i th a n H M G - C o A re d u c ta s e inhibito r, th e r e c o mme n d e d d o s e o f
W e lC h o l is 3 ta b l e ts ta ke n tw i c e p e r d a y w i th me a ls o r 6 ta b l e ts ta k e n o n c e pe r
d a y w i th a me a l.
H OW SUPPLI ED:
W e lC h o l is s u p p lie d a s a n o ff- w h ite , fi l m- c o a te d s o lid ta b le t imp rin te d w i th th e
w o r d "S a n k yo " o ve r "C 01 , " c o n ta in in g 6 2 5 mg c o le s e ve la m.
Marketed for: Sankyo Ptiarma Inc., NEWYork, NY 1 001 7
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Regression of secondary sexual character-
istics
Impaired sperm production.
Because many of these symptoms can be
attributed to aging or other medical causes,
they may be ignored by both patients and
physicians.
2
-^Recently, evidence has accumu-
lated that testosterone also plays an important
role in maintaining function with aging.
5
The Androgen Deficiency in Aging Males
(A DA M) Questionnaire, together with a
complete history and physical examination, is
useful in identifying patients who may benefit
from testing for hypogonadism (TABLE 1 ) .
6
OTHER CAUSES OF HYPOGONADI SM
Age is not the only cause of hypogonadism,
which has an estimated prevalence of 4 to 5
million men.
7
Other causes include primary
testicular failure (either congenital, develop-
mental, or acquired),
8
obesity, severe systemic
illnesses, malnutrition, AI DS, uremia, sickle
cell disease, or hepatic cirrhosis.4
TESTI NG FOR TESTOSTERONE
Plasma free testosterone tests are a good
measure of the amount of bioavailable testos-
terone because they measure serum testos-
terone unbound by sex hormone-binding
globulin. The traditional free testosterone
test is actually an analog assay and is not as
informative as a test that uses dialysis or ultra-
centrifugation (which is cheaper and easier to
perform than dialysis). The test that appears
to be most useful at present is the bioavailable
or weakly bound testosterone assay, which
measures both free and albumin-bound testos-
terone.
In contrast, the plasma total testosterone
level may be less informative because it mea-
sures both free testosterone and protein-
bound testosterone.
3
Thi s test can produce
normal readings even when age-related
increases in sex hormone-binding globulin
lower concentrations of bioavailable testos-
terone. I n addition, the test may have false-
positive results in insulin-resistant men,
because excess insulin lowers the concentra-
tion of sex hormone-binding globulin, which
can lower total testosterone levels even when
T A B L E 1
The ADAM* questi onnai re
1. Has your libido or sex drive decreased?
2. Do you have a lack of energy?
3. Have your strength or endurance decreased?
4. Have you lost weight?
5. Have you noticed a decreased enjoyment of life?
6. Are you sad or grumpy?
7. Are your erections less strong?
8. Have you noted a recent deterioration in your ability to play sports?
9. Do you fall asleep after dinner?
10. Has your work performance deteriorated recently?
Consider testosterone testing in any patient who answers "yes"
to questions 1 or 7, or to any three others.
' Androgen Deficiency in Agi ng Mal es
bioavailable testosterone is adequate.
Another option is the calculated free
testosterone index. This has been validated in
a recent study.
9
Healthy men experi ence wide hour-to-
hour and day-to-day fluctuations in testos-
terone levels (up to 20% over the course of
a week), so symptomatic men with normal
test results should be tested more than
once.
If any of these tests confirm testos-
terone deficiency, tests of gonadotropin lev-
els will help determine whether the cause of
the hypogonadi sm is primary (hyper-
gonadotropic hypogonadism) or secondary
to pi tui tary disease (hypogonadotropi c
hypogonadism). In the latter condi ti on,
gonadotropins fail to rise in response to low
testosterone levels.
Serum prolactin levels should also be
measured to screen for hyperprolactinemia.
Thi s can be caused by heart or renal failure,
hypothyroidism, or a number of drugs.
TESTOSTERONE THERAPY
The goals of testosterone therapy are to pro-
vide and maintain normal levels of testos-
terone, thus improving libido, psychological
disposition, body mass, strength, stamina, and
The bioavailable
testosterone
assay is
the test of
choice for
older men
880 CLEVELAND CLI NI C JOURNAL OF MEDI CI NE VOLUME 67 NUMBER 1 2 DECEMBER 2000
on September 24, 2014. For personal use only. All other uses require permission. www.ccjm.org Downloaded from
MEDI CAL GRAND ROUNDS
bone d e n s i t y .
2
-
3
, 1 0 Testosterone replacement
improves quality of life but probably does not
affect length of life.
Testosterone is available in oral capsules,
intramuscular injections, transdermal patch-
es, and transdermal gel.4 Unfortunatel y,
intramuscular injections can produce widely
fluctuating serum testosterone levels.
11
The
transdermal patch, although it provides more
physiologic testosterone levels, may cause
rashes.
12
The latest addition to our armamentari-
um is a 1% testosterone gel, available at
dosages of either 50 mg daily or 100 mg daily.
A large randomized trial found that this prod-
uct provided steadier serum testosterone con-
centrations than a 5 mg/ day transdermal
patch.
13
Using testosterone gel may also min-
imize skin reactions.
Both testosterone gel and the patch were
associated with improved libido within 30
days and continuing for up to 90 days. Gel
therapy was also associated with improved
mood and sense of well-being and a higher
level of sexual enjoyment.
Other documented effects of testosterone
therapy are increased upper body strength,
improved lipid balance, better memory, beard
growth, and coronary artery vasodilation. In a
mouse model of Alzheimer disease, testos-
terone reversed memory deficits by inhibiting
overproduction of amyloid precursor pro-
tein.'4 Testosterone may be beneficial for car-
diovascular risk factors and for benign prosta-
tic hyperplasia.
5
'
15
-
17
Testosterone may increase the hematocrit
and the risk of strokes. Testosterone therapy is
not indicated for men with prostatic cancer,
but there is no evidence that testosterone
increases the risk of prostate cancer.
REFERENCES
Elevated
prolactin
can be due
to heart or
renal failure,
hypothyroidism,
or a number
of drugs
1 . M o r l e y J E , K a i s e r FE , P e r r y H M 3 r d , e t a l .
L o n g i t u d i n a l c h a n g e s i n t e s t o s t e r o n e , l u t e i n i z i n g
h o r m o n e , a n d f o l l i c l e - s t i m u l a t i n g h o r m o n e i n
h e a l t h y o l d e r m e n . M e t a b C l i n E x p e r 1 9 9 7 ;
4 6 : 4 1 0 - 4 1 3 .
2 . M o r l e y J E , P e r r y H M 3 r d . A n d r o g e n d e fi c i e n c y i n
a g i n g m e n : r o l e o f t e s t o s t e r o n e r e p l a c e m e n t t h e r a -
p y . J L a b C l i n M e d 2 0 0 0 ; 1 3 5 : 3 7 0 - 3 7 8.
3 . T e n o v e r J L . M a l e h o r m o n e r e p l a c e m e n t t h e r a p y
i n c l u d i n g "a n d r o p a u s e . " E n d o c r i n o l M e t a b C l i n
N o r t h A m 1 9 9 8; 2 7 : 9 6 9 - 9 87 .
4 . P e t a k S M a n d t h e H y p o g o n a d i s m T a s k Fo r c e . A A C E
C l i n i c a l P r a c t i c e G u i d e l i n e s f o r t h e E v a l u a t i o n a n d
T r e a t m e n t o f H y p o g o n a d i s m i n A d u l t M a l e P a t i e n t s .
1 9 9 8. A v a i l a b l e a t h t t p : / / w w w . a a c e . c o m / c l i n / g u i d e s /
h y p o g o n a d i s m . h t m l . A c c e s s e d 6 / 2 3 / 0 0 .
5 . P e r r y H M 3 r d , M i l l e r D K , P a t r i c k P , M o r l e y J E .
T e s t o s t e r o n e a n d l e p t i n i n o l d e r A f r i c a n - A m e r i c a n
m e n : r e l a t i o n s h i p t o a g e , s t r e n g t h , f u n c t i o n , a n d
s e a s o n . M e t a b C l i n E x p e r 2 0 0 0 ; 4 9 : 1 0 85 - 1 0 9 1 .
6 . M o r l e y J E , C h a r l t o n E , P a t r i c k P , e t a l . V a l i d a t i o n o f
a s c r e e n i n g q u e s t i o n n a i r e f o r a n d r o g e n d e fi c i e n c y
i n a g i n g m a l e s ( A D A M ) [a b s t r a c t ]. P r o c A m
E n d o c r i n e S o c 1 9 9 8; a b s t r a c t P 2 - 6 4 9 .
7 . U S Fo o d a n d D r u g A d m i n i s t r a t i o n U p d a t e s . S k i n
p a t c h r e p l a c e s t e s t o s t e r o n e . F o o d a n d D r u g
A d m i n i s t r a t i o n W e b S i t e . A v a i l a b l e a t :
h t t p : / / w w w . f d a . g o v . A c c e s s e d N o v e m b e r 2 , 2 0 0 0 .
8. W i n t e r s S J . C u r r e n t s t a t u s o f t e s t o s t e r o n e r e p l a c e -
m e n t t h e r a p y i n m e n . A r c h Fa m M e d 1 9 9 9 ;
8: 2 5 7 - 2 6 3 .
9 . V e r m e u l e n A , V e r d o n c k L , K a u f m a n J M . A c r i t i c a l
e v a l u a t i o n o f s i m p l e m e t h o d s f o r t h e e s t i m a t i o n o f
fr e e t e s t o s t e r o n e i n s e r u m . J C l i n E n d o c r i n o l M e t a b
1 9 9 9 ; 84 : 3 6 6 6 - 3 6 7 2 .
1 0 . S i h R , M o r l e y J E , K a i s e r FE , P e r r y H M 3 r d , P a t r i c k P ,
R o s s C . T e s t o s t e r o n e r e p l a c e m e n t i n o l d e r h y p o g o -
n a d a l m e n : a 1 2 - r r i o n t h r a n d o m i z e d c o n t r o l l e d t r i a l .
J C l i n E n d o c r i n o l M e t a b 1 9 9 7 ; 82 : 1 6 6 1 - 1 6 6 7 .
1 1 . B e h r e H M , N e i s c h l a g E . C o m p a r a t i v e p h a r m a c o k i -
n e t i c s o f t e s t o s t e r o n e e s t e r s . I n : N B e h r e H M ,
N i e s c h l a g E , e d i t o r s . T e s t o s t e r o n e : A c t i o n ,
D e fi c i e n c y , S u b s t i t u t i o n . B e r l i n , G e r m a n y : S p r i n g e r -
V e r l a g ; 1 9 9 8: 3 2 9 - 3 4 8.
1 2 . A n d r o d e r m p r o d u c t i n f o r m a t i o n . P h y s i c i a n s ' D e s k
R e fe r e n c e . 5 4 t h e d , M o n t v a l e , N J : M e d i c a l
E c o n o m i c s C o ; 2 0 0 0 : 3 1 7 0 - 3 1 7 2 .
1 3 . W a n g C , B e r m a n N , L o n g s t r e t h J A , e t a l .
P h a r m a c o k i n e t i c s o f t r a n s d e r m a l t e s t o s t e r o n e g e l
i n h y p o g o n a d a l n n e n : a p p l i c a t i o n o f g e l a t o n e
s i t e v e r s u s f o u r s i t e s : A G e n e r a l C l i n i c a l R e s e a r c h
C e n t e r S t u d y . J C l i n E n d o c r i n o l M e t a b 2 0 0 0 ;
85 : 9 6 4 - 9 6 9 .
1 4 . F l o o d J F, Fa r r S A , K a i s e r FE , L a R e g l n a M , M o r l e y J E .
A g e - r e l a t e d d e c r e a s e o f p l a s m a t e s t o s t e r o n e i n
S A M P 8 m i c e : r e p l a c e m e n t i m p r o v e s a g e - r e l a t e d
i m p a i r m e n t o f l e a r n i n g a n d m e m o r y . P h y s i o l B e h a v
1 9 9 5 ; 5 7 : 6 6 9 - 6 7 3 .
1 5 . H a r t n e l l J , K o r e n m a n S G , V i o s c a S P . R e s u l t s o f
t e s t o s t e r o n e e n a n t h a t e t h e r a p y i n o l d e r m e n . P r o c
7 2 n d A n n M e e t i n g E n d o c r i n e S o c 1 9 9 0 : 4 2 8.
1 6 . H a j j a r R R , K a i s e r FE , M o r l e y J E . O u t c o m e s o f l o n g -
t e r m t e s t o s t e r o n e r e p l a c e m e n t i n o l d e r h y p o g o -
n a d a l m a l e s : a r e t r o s p e c t i v e a n a l y s i s . J C l i n
E n d o c r i n o l M e t a b 1 9 9 7 ; 82 : 3 7 9 3 - 3 7 9 6 .
1 7 . W u S , W e n g X . R e g u l a t i o n o f a t r i a l n a t r i u r e t i c p e p -
t i d e , t h r o m b o x a n e , a n d p r o s t a g l a n d i n p r o d u c t i o n
b y a n d r o g e n i n e l d e r l y m e n w i t h c o r o n a r y h e a r t d i s -
e a s e . C h i n M e d S c i J 1 9 9 3 ; 8: 2 0 7 - 2 0 9 .
ADDRESS: John E. Morley, MB, BCh, St. Louis University Health
Sciences Center, 1402 South Grand Boulevard, Room M238, St.
Louis, MO 63104.
8 8 2 CLEVELAND CLI NI C JOURNAL OF MEDI CI NE VOLUME 67 NUMBER 1 2 DECEMBER 2000
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REMICADE
( i n f l i x i m a b )
fo r I V I n j e c t i o n
B R I E F S U M M A R Y
S e e p a c k a g e I n s e r t fo r fu l l p r e s c r i b i n g i n fo r m a t i o n .
I N D I C A T I O N S A N D U S A G E : R h e u m a to i d A r th r i ti s R E M I C A D E , i n c o m b i n a ti o n w i t h m e th o tr e x a te , is i n d i c a te d fo r th e
r e d u c ti o n In s i g n s a n d s y m p t o m s o f r h e u m a to i d a r th r i ti s i n p a ti e n ts w h o ha ve h a d a n in a d e q u a te r e s p o n s e to m e th o tr e x -
a te . C r o h n 's D is e a s e R E M I C A D E i s i n d i c a te d fo r th e r e d u c ti o n in s i g n s a n d s y m p t o m s o f C r o h n 's d is e a s e i n p a ti e n ts w i th
m o d e r a te l y to s e v e r e l y a c ti v e C r o h n 's d is e a s e w h o h a ve h a d a n I n a d e q u a te r e s p o n s e t o c o n v e n ti o n a l th e r a p y . T h e s a f e -
t y a n d e f f i c a c y o f t h e r a p y c o n t i n u e d b e y o n d a s i n g l e d o s e h a v e n o t b e e n e s t a b l i s h e d . R E M I C A D E i s i n d i c a te d fo r
th e r e d u c ti o n i n th e n u m b e r o f d r a i n i n g e n te r o c u ta n e o u s fi s tu l a e i n p a ti e n ts w i t h fi s tu l i z i n g C r o h n ' s d i s e a s e . T h e
s a f e t y a n d e f f i c a c y o f t h e r a p y c o n t i n u e d b e y o n d t h r e e d o s e s h a v e n o t b e e n s t u d i e d .
C O N T R A I N D I C A T I O N S : R E M I C A D E s h o u l d n o t be a d m i n i s te r e d to p a ti e n ts w i t h k n o w n h y p e r s e n s i ti v i ty to a n y m u r i n e
p r o te i n s o r o th e r c o m p o n e n t o f th e p r o d u c t.
W A R N I N G S :
R I S K O F I N F E C T I O N S
S E R I O U S I N F E C T I O N S , I N C L U D I N G S E P S I S A N D F A T A L I N F E C T I O N S , H A V E B E E N R E P O R T E D I N P A T I E N T S
R E C E I V I N G T N F - B L O C K I N G A G E N T S . M A N Y O F T H E S E R I O U S I N F E C T I O N S I N P A T I E N T S T R E A T E D W I T H
R E M I C A D E H A V E O C C U R R E D I N P A T I E N T S O N C O N C O M I T A N T I M M U N O S U P P R E S S I V E T H E R A P Y T H A T , I N A D D I -
T I O N T O T H E I R C R O H N ' S D I S E A S E O R R H E U M A T O I D A R T H R I T I S , C O U L D P R E D I S P O S E T H E M T O I N F E C T I O N S .
C A U T I O N S H O U L D B E E X E R C I S E D W H E N C O N S I D E R I N G T H E U S E O F R E M I C A D E I N P A T I E N T S W I T H A C H R O N I C
I N F E C T I O N O R A H I S T O R Y O F R E C U R R E N T I N F E C T I O N . R E M I C A D E S H O U L D N O T B E G I V E N T O P A T I E N T S W I T H A
C L I N I C A L L Y I M P O R T A N T , A C T I V E I N F E C T I O N . P A T I E N T S W H O D E V E L O P A N E W I N F E C T I O N W H I L E U N D E R G O I N G
T R E A T M E N T W I T H R E M I C A D E S H O U L D B E M O N I T O R E D C L O S E L Y . I F A P A T I E N T D E V E L O P S A S E R I O U S I N F E C -
T I O N O R S E P S I S , R E M I C A D E T H E R A P Y S H O U L D B E D I S C O N T I N U E D ( s e e ADVERSE REACTIONS, Medians).
H y p e r s e n s i t i v i t y R E M I C A D E h a s b e e n a s s o c i a te d w i t h h y p e r s e n s i ti v i ty r e a c ti o n s th a t v a r y i n th e i r t i m e o f o n s e t. M o s t
h y p e r s e n s i ti v i ty r e a c ti o n s , w h i c h i n c l u d e u r ti c a r i a , d y s p n e a a n d / o r h y p o te n s i o n , h a ve o c c u r r e d d u r i n g o r w i t h i n 2
h o u r s o f i n fl i x i m a b i n fu s i o n . H o w e v e r, In s o m e c a s e s , s e r u m s i c k n e s s - l i k e r e a c ti o n s h a ve b e e n o b s e r v e d In C r o h n 's
d i s e a s e p a ti e n ts 3 to 12 d a y s a fte r R E M I C A D E th e r a p y w a s r e i n s tl tu te d fo l l o w i n g a n e x te n d e d p e r i o d w i th o u t
R E M I C A D E tr e a tm e n t. S y m p t o m s a s s o c i a te d w i t h th e s e r e a c ti o n s i n c l u d e l e v e r , r a s h , h e a d a c h e , s o r e th r o a t, m y a l -
g i a s , p o l y a r th r a l g i a s , h a n d a n d fa c i a l e d e m a a n d / o r d y s p h a g i a . T h e s e r e a c ti o n s w e r e a s s o c i a te d w i t h m a r k e d i n c r e a s e
i n a n ti b o d i e s t o i n fl i x i m a b , l o s s o f d e te c ta b l e s e r u m c o n c e n tr a ti o n s o f R E M I C A D E , a n d p o s s i b l e l o s s o f d r u g e ffi c a -
c y. R E M I C A D E s h o u l d be d i s c o n ti n u e d fo r s e v e r e r e a c ti o n s . M e d i c a ti o n s fo r th e tr e a tm e n t o f h y p e r s e n s i ti v i ty re a c -
t i o n s ( e . g . , a c e ta m i n o p h e n , a n ti h i s ta m i n e s , c o r ti c o s te r o i d s a n d / o r e p i n e p h r i n e ) s h o u l d be a v a i l a b l e fo r i m m e d i a te u s e
I n th e e v e n t o f a r e a c ti o n (s e e ADVERSE REACTIONS, Infusion-related Reactions).
P R E C A U T I O N S : A u t o i m m u n i t y T r e a tme n t w i t h R E M I C A D E m a y r e s u l t I n th e fo r m a t i o n o f a u to a n ti b o d i e s a n d , ra re l y,
i n th e d e v e l o p m e n t of a l u p u s - l i k e s y n d r o m e . I f a p a ti e n t d e v e l o p s s y m p t o m s s u g g e s ti v e o f a l u p u s - l i k e s y n d r o m e
fo l l o w i n g t r e a t m e n t w i t h R E M I C A D E , t r e a t m e n t s h o u l d b e d i s c o n t i n u e d ( s e e ADVERSE REACTIONS,
Autoantibodies/Lupus-like Syndrome). M a l i g n a n c y P a ti e n ts w i t h l o n g d u r a ti o n o fC r o h n ' s d i s e a s e o r r h e u m a to i d
a r t h r i t i s a n d c h r o n i c e x p o s u r e t o i m m u n o s u p p r e s s a n t th e r a p i e s a re m o r e p r o n e to d e v e l o p l y m p h o m a s (s e e
ADVERSE REACTIONS, MalignanciesAymphoprollferative Disease). T h e i m p a c t o f tr e a tm e n t w i t h R E M I C A D E o n
th e s e p h e n o m e n a i s u n k n o w n . I m m u n o g e n i c i t y T r e a tm e n t w i t h R E M I C A D E c a n b e a s s o c i a te d w i t h t h e d e v e l o p m e n t
o f a n ti b o d i e s t o i n fl i x i m a b ( a l s o r e fe r r e d t o a s h u m a n a n tl c h i m e r i c a n ti b o d i e s , H A C A ) . O n e h u n d r e d t h i r t y - fo u r o f
th e 1 9 9 C r o h n ' s d i s e a s e p a ti e n ts tr e a te d w i t h R E M I C A D E w e r e e v a l u a te d fo r th e d e v e l o p m e n t o f i n fl i x i m a b - s p e c i fi c
a n ti b o d i e s ; 1 8 ( 1 3 %) w e r e a n ti b o d y - p o s i ti v e ( th e m a j o r i ty a t l o w l i te r , <1 : 2 0 ) . P a ti e n ts w h o w e r e a n ti b o d y - p o s i ti v e
w e r e m o r e l i k e l y to e x p e r i e n c e a n i n fu s i o n r e a c ti o n (s e e ADVERSE REACTIONS, Intusm-related Reactions ).
A n ti b o d y d e v e l o p m e n t w a s l o w e r a m o n g r h e u m a to i d a r t h r i t i s a n d C r o h n 's d i s e a s e p a ti e n ts r e c e i v i n g I m m u n o s u p -
p r e s s a n t th e r a p i e s s u c h a s 6 - M P , A Z A o r M T X . W i th r e p e a te d d o s i n g o f R E M I C A D E , s e r u m c o n c e n tr a ti o n s o f
i n fl i x i m a b w e r e h i g h e r In r h e u m a to i d a r th r i ti s p a ti e n ts w h o r e c e i v e d c o n c o m i ta n t M T X T h e r e a re l i m i te d d a ta a v a i l -
a b l e o n th e d e v e l o p m e n t o f a n ti b o d i e s t o i n fl i x i m a b i n p a ti e n ts r e c e i v i n g l o n g - t e r m tr e a tm e n t w i t h R E M I C A D E .
B e c a u s e i m m u n o g e n i c s a n a l y s e s a re p r o d u c t- s p e c i fi c , c o m p a r i s o n o l a n ti b o d y ra te s to th o s e fr o m o th e r p r o d u c ts
is n o t a p p r o p r i a te . V a c c i n a t i o n s N o d a ta a r e a v a i l a b l e o n th e r e s p o n s e t o v a c c i n a ti o n o r o n th e s e c o n d a r y tr a n s m i s -
s i o n o f i n fe c ti o n b y live v a c c i n e s i n p a ti e n ts r e c e i v i n g a n ti - T N F th e r a p y . I t I s r e c o m m e n d e d th a t live v a c c i n e s n o t be
g i v e n c o n c u r r e n tl y . D r u g I n t e r a c t i o n s S p e c i fi c d r u g i n te r a c ti o n s tu d i e s , i n c l u d i n g I n te r a c ti o n s w i t h M T X , h a ve n o t
b e e n c o n d u c te d . T h e m a j o r i ty o fp a ti e n ts i n r h e u m a to i d a r th r i ti s o r C r o h n 's d i s e a s e c l i n i c a l tr i a l s r e c e i v e d o n e o r
m o r e c o n c o m i t a n t m e d i c a ti o n s . I n r h e u m a to i d a r th r i ti s , c o n c o m i t a n t m e d i c a ti o n s b e s i d e s M T X w e r e n o n s te r o i d a l
a n t i - i n fl a m m a t o r y a g e n ts , fo l i c a c i d , c o r ti c o s te r o i d s a n d / o r n a r c o ti c s . C o n c o m i ta n t C r o h n 's d i s e a s e m e d i c a ti o n s w e r e
a n ti b i o ti c s , a n ti v i r a l s , c o r ti c o s te r o i d s , 6 - M P / A Z A a n d a m i n o s a l i c y l a te s . P a ti e n ts w i t h C r o h n 's d i s e a s e w h o re c e i v e d
I m m u n o s u p p r e s s a n ts te n d e d t o e x p e r i e n c e fe w e r i n fu s i o n r e a c ti o n s c o m p a r e d t o p a ti e n ts o n n o i m m u n o s u p p r e s -
s a n ts ( s e e PRECAUTIONS, Immunogenicity a n d ADVERSE REACTIONS, Infusion-related Reactions).
C a r c i n o g e n e s i s , M u t a g e n e s i s a n d I m p a i r m e n t o f F e r t i l i t y L o n g - t e r m s tu d i e s i n a n i m a l s ha ve n o t b e e n p e r fo r m e d
t o e v a l u a te th e c a r c i n o g e n i c p o te n ti a l . N o c l a s to g e n i c o r m u ta g e n i c e ffe c ts o f I n fl i x i m a b w e r e o b s e r v e d i n th e in vivo
m o u s e m i c r o n u c l e u s te s t o r th e Salmonella-Escherichia coii ( A m e s ) a s s a y , r e s p e c ti v e l y . C h r o m o s o m a l a b e r r a ti o n s
w e r e n o t o b s e r v e d In a n a s s a y p e r fo r m e d u s i n g h u m a n l y m p h o c y te s . I t i s n o t k n o w n w h e th e r i n fl i x i m a b c a n i m p a i r
fe r ti l i ty i n h u m a n s . N o i m p a i r m e n t o f fe r ti l i ty w a s o b s e r v e d i n a fe r ti l i ty a n d g e n e r a l r e p r o d u c ti o n t o x i c i t y s tu d y c o n -
d u c te d i n m i c e u s i n g a n a n a l o g o u s a n ti b o d y th a t s e l e c ti v e l y i n h i b i ts th e fu n c ti o n a l a c ti v i ty o f m o u s e T N Fa , P r e g n a n c y
C a t e g o r y C S i n c e i n fl i x i m a b d o e s n o t c r o s s - r e a c t w i th T N Fa I n s p e c i e s o th e r th a n h u m a n s a n d c h i m p a n z e e s , a n i m a l
r e p r o d u c ti o n s tu d i e s h a ve n o t b e e n c o n d u c te d w i t h R E M I C A D E . I t i s n o t k n o w n w h e th e r R E M I C A D E c a n c a u s e fe ta l
h a r m w h e n a d m i n i s te r e d to a p r e g n a n t w o m a n o r c a n a ffe c t r e p r o d u c ti o n c a p a c i ty w h i l e i n fl i x i m a b i s p r e s e n t in th e
s e r u m . R E M I C A D E s h o u l d be g i v e n to a p r e g n a n t w o m a n o n l y i f c l e a r l y n e e d e d . N o e v i d e n c e o fm a te r n a l to x i c i ty ,
e m b r y o to x i c i ty o r te r a to g e n i c i ty w a s o b s e r v e d i n a d e v e l o p m e n ta l to x i c i ty s tu d y c o n d u c te d i n m i c e u s i n g a n a n a l o -
g o u s a n ti b o d y th a t s e l e c ti v e l y i n h i b i ts th e fu n c ti o n a l a c ti v i ty o f m o u s e T N Fa . N u r s i n g M o t h e r s I t i s n o t k n o w n
w h e th e r I n fl i x i m a b is e x c r e te d i n h u m a n m i l k o r a b s o r b e d s y s te m l c a l l y a fte r i n g e s ti o n . B e c a u s e m a n y d r u g s a n d
i m m u n o g l o b u l i n s a re e x c r e te d i n h u m a n m i l k , a n d b e c a u s e o f th e p o te n ti a l fo r a d v e r s e r e a c ti o n s i n n u r s i n g i n fa n ts
fr o m R E M I C A D E , a d e c i s i o n s h o u l d be m a d e w h e th e r t o d i s c o n ti n u e n u r s i n g o r t o d i s c o n ti n u e th e d r u g , ta k i n g i n to
a c c o u n t th e I m p o r ta n c e o f th e d r u g t o th e m o th e r . P e d i a t r i c U s e S a fe ty a n d e ffe c ti v e n e s s o f R E M I C A D E i n p a ti e n ts
w i t h j u v e n i l e r h e u m a to i d a r th r i ti s a n d i n p e d i a tr i c p a ti e n ts w i t h C r o h n ' s d i s e a s e h a v e n o t b e e n e s ta b l i s h e d . G e r i a t r i c
U s e I n th e A T T R A C T s tu d y , n o o v e r a l l d i ffe r e n c e s w e r e o b s e r v e d i n e ffe c ti v e n e s s o r s a fe ty I n th e 7 2 p a ti e n ts a g e d 6 5
o r o l d e r c o m p a r e d t o y o u n g e r p a ti e n ts . I n C r o h n 's d i s e a s e s tu d i e s , th e r e w e r e i n s u ffi c i e n t n u m b e r s o f p a ti e n ts a g e d
6 5 o r o l d e r t o d e te r m i n e w h e th e r th e y r e s p o n d d i ffe r e n tl y fr o m p a ti e n ts a g e d 1 8 t o 6 5 . B e c a u s e th e r e is a h i g h e r
i n c i d e n c e o f i n fe c ti o n s i n th e e l d e r l y p o p u l a ti o n i n g e n e r a l , c a u ti o n s h o u l d b e u s e d i n tr e a ti n g th e e l d e r l y ( s e e
ADVERSE REACTIONS, Infections).
A D V E R S E R E A C T I O N S : A to ta l o f 7 7 1 p a ti e n ts w e r e tr e a te d w i t h R E M I C A D E I n c l i n i c a l tr i a l s . I n b o th r h e u m a to i d
a r th r i ti s a n d C r o h n ' s d i s e a s e tr i a l s , a p p r o x i m a te l y 5 % o f p a ti e n ts d i s c o n ti n u e d R E M I C A D E b e c a u s e o f a d v e r s e
e x p e r i e n c e s . T h e m o s t c o m m o n r e a s o n s fo r d i s c o n ti n u a ti o n o f tr e a tm e n t w e r e d y s p n e a , u r ti c a r i a a n d h e a d a c h e .
I n f u s i o n - r e l a t e d R e a c t i o n s Acute infusion reactions A n i n fu s i o n r e a c ti o n w a s d e fi n e d a s a n y a d v e r s e e ve n t o c c u r r i n g
d u r i n g th e I n fu s i o n o r w i th i n 1 t o 2 h o u r s a fte r th e I n fu s i o n . S e v e n te e n p e r c e n t o f R E M I C A D E - tr e a te d p a ti e n ts i n
a ll c l i n i c a l t r i a l s e x p e r i e n c e d a n i n fu s i o n r e a c ti o n c o m p a r e d t o 7 % o f p l a c e b o - tr e a te d p a ti e n ts . A m o n g th e 3 2 84
R E M I C A D E i n fu s i o n s , 4 % w e r e a c c o m p a n i e d b y n o n s p e c i fi c s y m p t o m s s u c h a s fe v e r o r c h i l l s , 1 % w e r e a c c o m p a n i e d
b y p r u r i t u s o r u r ti c a r i a , 1 % w e r e a c c o m p a n i e d b y c a r d i o p u l m o n a r y r e a c ti o n s ( p r i m a r i l y c h e s t p a i n , h y p o te n s i o n ,
h y p e r te n s i o n o r d y s p n e a ) , a n d 0 . 1 % w e r e a c c o m p a n i e d b y c o m b i n e d s y m p t o m s o f p r u r i tu s / u r ti c a r i a a n d c a r d i o p u l -
m o n a r y r e a c ti o n s . L e s s th a n 2 % o f p a ti e n ts d i s c o n ti n u e d R E M I C A D E b e c a u s e o f i n fu s i o n r e a c ti o n s , a n d a l l p a ti e n ts
r e c o v e r e d w i t h tr e a tm e n t a n d / o r d i s c o n ti n u a ti o n o f i n fu s i o n . R E M I C A D E i n fu s i o n s b e y o n d th e i n i ti a l i n fu s i o n i n
r h e u m a to i d a r th r i ti s p a ti e n ts w e r e n o t a s s o c i a te d w i th a h i g h e r I n c i d e n c e o f r e a c ti o n s . P a ti e n ts w i th C r o h n ' s d i s e a s e
w h o b e c a m e p o s i ti v e fo r a n ti b o d i e s to i n fl i x i m a b w e r e m o r e l i k e l y t o d e v e l o p i n fu s i o n r e a c ti o n s th a n w e r e th o s e w h o
w e r e n e g a ti v e ( 3 6 % v s . 1 1 % r e s p e c ti v e l y ) . U s e o f c o n c o m i t a n t I m m u n o s u p p r e s s a n t a g e n ts a p p e a r e d t o r e d u c e th e
fr e q u e n c y o f a n ti b o d i e s t o i n fl i x i m a b a n d i n fu s i o n r e a c ti o n s ( s e e PRECAUTIONS, Immunogenicity a n d Drug
Interactions). Reactions following readministration I n a c l i n i c a l tr i a l o f fo r ty p a ti e n ts w i th C r o h n 's d i s e a s e r e tr e a te d
w i t h i n fl i x i m a b fo l l o w i n g a 2 t o 4 y e a r p e r i o d w i t h o u t i n fl i x i m a b tr e a tm e n t, 1 0 p a ti e n ts e x p e r i e n c e d a d v e r s e e v e n ts
m a n i fe s ti n g 3 t o 1 2 d a y s fo l l o w i n g I n fu s i o n o f w h i c h 6 w e r e c o n s i d e r e d s e r i o u s . S i g n s a n d s y m p t o m s i n c l u d e d m y a l -
g i a a n d / o r a r th r a l g i a w i t h l e v e r a n d / o r r a s h , w i t h s o m e p a ti e n ts a l s o e x p e r i e n c i n g p r u r i tu s , l a c i a l , h a n d o r l i p e d e m a ,
d y s p h a g i a , u r ti c a r i a , s o r e th r o a t, a n d h e a d a c h e . P a ti e n ts e x p e r i e n c i n g th e s e a d v e r s e e v e n ts h a d n o t e x p e r i e n c e d i n fu -
s i o n - r e l a te d a d v e r s e e v e n ts a s s o c i a te d w i t h t h e i r i n i ti a l i n fl i x i m a b th e r a p y . O f th e 4 0 p a ti e n ts e n r o l l e d , th e s e a d v e r s e
e v e n ts o c c u r r e d i n 9 o f 2 3 ( 3 9 %) w h o h a d re c e i v e d l i q u i d fo r m u l a t i o n w h i c h i s no l o n g e r i n u s e a n d 1 o f 1 7 ( 6 %)
w h o r e c e i v e d l y o p h i l l z e d fo r m u l a ti o n . T h e c l i n i c a l d a ta a re n o t a d e q u a te t o d e te r m i n e if o c c u r r e n c e o f th e s e r e a c ti o n s
is d u e t o d i ffe r e n c e s in fo r m u l a ti o n . P a ti e n ts ' s i g n s a n d s y m p t o m s i m p r o v e d s u b s ta n ti a l l y o r r e s o l v e d w i t h tr e a tm e n t
i n a l l c a s e s . T h e re a re i n s u ffi c i e n t d a ta o n th e i n c i d e n c e o f th e s e e v e n ts a fte r d r u g - fr e e i n te r v a l s o l le s s th a n 2 y e a r s .
H o w e v e r , th e s e e v e n ts h a ve b e e n o b s e r v e d i n fr e q u e n tl y i n c l i n i c a l tr i a l s a n d p o s t - m a r k e t i n g s u r v e i l l a n c e a t i n te r v a l s
o f l e s s th a n 1 ye a r. I n fe c t i o n s I n R E M I C A D E ( i n fl i x i m a b ) c l i n i c a l tr i a l s . I n fe c ti o n s w e r e r e p o r te d by 2 6 % o f
R E M I C A D E - tr e a te d p a ti e n ts ( a v e ra g e o l 2 7 w e e k s o f fo l l o w - u p ) a n d b y 1 6 % o f p l a c e b o - tr e a te d p a ti e n ts ( a v e ra g e o f
2 0 w e e k s o f fo l l o w - u p ) . T h e i n fe c ti o n s m o s t fr e q u e n tl y r e p o r te d w e r e u p p e r r e s p i r a to r y tr a c t i n fe c ti o n s ( i n c l u d i n g ,
s i n u s i ti s , p h a r y n g i ti s , a n d b r o n c h i ti s ) a n d u r i n a r y tr a c t i n fe c ti o n s . N o i n c r e a s e d r i s k o f s e r i o u s i n fe c ti o n s o r s e p s i s
h a s b e e n o b s e r v e d w i t h R e m i c a d i c o m p a r e d t o p l a c e b o . A m o n g R E M I C A D E - tr e a te d p a ti e n ts , th e s e s e r i o u s i n fe c ti o n s
i n c l u d e d p n e u m o n i a , c e l l u l i ti s , p y e l o n e p h r i ti s a n d s e p s i s . I n th e A T T R A C T s tu d y , o n e p a ti e n t d i e d w i t h d i s s e m i n a te d
tu b e r c u l o s i s a n d o n e d i e d w i t h d i s s e m i n a te d c o c c i d i o i d o m y c o s i s . T h e r e l a ti o n s h i p to R E M I C A D E is u n k n o w n (s e e
WARNINGS, Risk ol Infections). T we lve p e r c e n t o f p a ti e n ts w i t h fi s tu l i z i n g C r o h n 's d i s e a s e d e v e l o p e d a n e w a b s c e s s
8 t o 1 6 w e e k s a fte r th e l a s t i n fu s i o n o f R E M I C A D E . A u l o a n t i b o d i e s / L u p u s - 1 i k e S y n d r o m e P a ti e n ts w e r e te s te d fo r
a u to a n ti b o d i e s a t m u l ti p l e t i m e p o i n ts . I n th e r h e u m a to i d a r t h r i t i s A T T R A C T s tu d y , 2 3 % o f R E M I C A D E - tr e a te d
p a ti e n ts d e v e l o p e d a n ti n u c l e a r a n ti b o d i e s ( A N A ) b e tw e e n s c r e e n i n g a n d l a s t e v a l u a ti o n , c o m p a r e d to 6 % o f p l a c e b o -
tr e a te d p a ti e n ts . A n ti - d s D N A a n ti b o d i e s d e v e l o p e d i n a p p r o x i m a te l y 4 % o f R E M I C A D E - tr e a te d p a ti e n ts , c o m p a r e d to
n o n e o f th e p l a c e b o - tr e a te d p a ti e n ts . N o a s s o c i a ti o n w a s s e e n b e tw e e n R E M I C A D E d o s e / s c h e d u l e a n d d e v e l o p m e n t
o f A N A o r a n tl - d s D N A . O f C r o h n 's d i s e a s e p a ti e n ts tr e a te d w i t h R E M I C A D E w h o w e r e e v a l u a te d fo r a n ti n u c l e a r a n ti -
b o d i e s ( A N A ) , 3 4 % d e v e l o p e d A N A b e tw e e n s c r e e n i n g a n d l a s t e v a l u a ti o n . A n ti - d s D N A a n ti b o d i e s d e v e l o p e d i n
a p p r o x i m a te l y 9 % o l C r o h n ' s d i s e a s e p a ti e n ts tr e a te d w i th R E M I C A D E . T h e d e v e l o p m e n t o f a n ti - d s D N A a n ti b o d i e s
w a s n o t r e l a te d t o e i th e r th e do s e o r d u r a ti o n o f R E M I C A D E tr e a tm e n t. H o w e v e r , b a s e l i n e th e r a p y w i t h a n i m m u n o -
s u p p r e s s a n t i n C r o h n 's d i s e a s e p a ti e n ts w a s a s s o c i a te d w i th r e d u c e d d e v e l o p m e n t o l a n ti - d s D N A a n ti b o d i e s ( 3 %
c o m p a r e d to 2 1 % i n p a ti e n ts n o t r e c e i v i n g a n y i m m u n o s u p p r e s s a n t ) . C r o h n ' s d i s e a s e p a ti e n ts w e r e a p p r o x i m a te l y
2 ti m e s m o r e l i k e l y t o d e v e l o p a n tl - d s D N A a n ti b o d i e s it th e y w e r e A N A - p o s l ti v e a t s t u d y e n t i y . T h re e p a ti e n ts d e v e l -
o p e d c l i n i c a l s y m p t o m s c o n s i s te n t w i t h a l u p u s - l i k e s y n d r o m e , t w o w i t h r h e u m a to i d a r th r i ti s a n d o n e w i t h C r o h n 's
d i s e a s e . A l l th r e e p a ti e n ts I m p r o v e d fo l l o w i n g d i s c o n ti n u a ti o n o l th e r a p y a n d a p p r o p r i a te m e d i c a l tr e a tm e n t (s e e
PRECAUTIONS, Autoimmunity). M a l i g n a n c i e s / L y m p h o p r o l l l e r a t l v e D i s e a s e Five n e w a n d 2 r e c u r r e n t m a l i g n a n c i e s
w e r e o b s e r v e d i n 6 of 7 7 1 p a ti e n ts tr e a te d w i th R E M I C A D E l o r u p to 3 6 w e e k s i n c l i n i c a l tr i a l s . T h e s e w e r e n o n -
H o d g k i n ' s B - c e l l l y m p h o m a , b re a s t c a n c e r, m e l a n o m a , s q u a m o u s c e l l c a n c e r o f th e s k i n , a n d b a s a l c e l l c a n c e r . T h e r e
a r e I n s u ffi c i e n t d a ta to d e te r m i n e w h e th e r R E M I C A D E c o n tr i b u te d t o th e d e v e l o p m e n t o f th e s e m a l i g n a n c i e s . T h e
o b s e r v e d ra te s a n d i n c i d e n c e s w e re s i m i l a r t o th o s e e x p e c te d fo r th e p o p u l a ti o n s s t u d i e d '
2
(s e e PRECAUTIONS,
Malignancy). O t h e r A d v e r s e R e a c t i o n s A d v e r s e e v e n ts o c c u r r i n g a t a fr e q u e n c y o f a t le a s t 5 % i n t r i a l s i n p a ti e n ts
w i t h r h e u m a to i d a r th r i ti s o r C ro h n 's d i s e a s e a re s h o w n i n th e ta b l e b e l o w . P a ti e n ts w i th C r o h n ' s d i s e a s e w h o w e r e
tr e a te d w i t h R E M I C A D E w e r e m o r e l i k e l y th a n p a ti e n ts w i t h r h e u m a to i d a r t h r i t i s t o e x p e r i e n c e a d v e r s e e v e n ts a s s o -
c i a te d w i t h g a s tr o i n te s ti n a l s y m p t o m s .
A D V E R S E E V E N T S I N R H E U M A T O I D A R T H R I T I S A N D C R O H N 'S D I S E A S E T R I A L S
R H E U M A T O I D A R T H R I T I S C R O H N 'S D I S E A S E
P l a c e b o R E M I C A D E P l a c e b o R E M I C A D E
( n =1 3 3 ) ( n = 5 5 5 ) ( n =5 6 ) ( n =1 9 9 )
A v g . w e e k s o f fo l l o w - u p 2 2 . 3 2 6 . 9 1 4 . 7 2 7 . 0
R e s p i r a to r y
U p p e r r e s p i r a to r y i n fe c ti o n 1 3 % 2 0 % 9 % 1 6 %
C o u g h i n g 5 % 1 0 % 0 % 5 %
S i n u s i ti s 3 % 9 % 2 % 5 %
R h i n i ti s 4 % 8% 4 % 6 %
P h a r y n g i ti s 5 % 8% 5 % 9 %
B r o n c h i ti s 2 % 4 % 2 % 7 %
G a s tr o i n te s ti n a l
N a u s e a 1 7 % 1 4 % 4 % 1 7 %
A b d o m i n a l P a i n 7 % 8% 4 % 1 2 %
V o m i t i n g 1 0 % 5 % 0 % 9 %
O th e r
H e a d a c h e 1 0 % 2 0 % 2 1 % 2 3 %
R a s h 4 % 9 % 5 % 6 %
Fa ti g u e 5 % 6 % 5 % 1 1 %
Fe ve r 4 % 6 % 7 % 1 0 %
B a c k p a in 2 % 6 % 4 % 5 %
P a i n 4 % 6 % 5 % 9 %
U r i n a r y tr a c t i n fe c ti o n 3 % 6 % 4 % 3 %
P r u r i tu s 0 % 5 % 2 % 5 %
M o n i l i a s i s 2 % 3 % 0 % 5 %
S e r i o u s a d v e r s e e v e n ts b y b o d y s y s te m th a t o c c u r r e d I n a l l p a ti e n ts tr e a te d w i t h R E M I C A D E a t fr e q u e n c i e s <2 % a re
a s fo l l o w s :
Body as a whole: a b d o m i n a l h e rn ia , c h e s t p a i n , fa l l , p a in Blood: s p l e n i c i n fa r c ti o n , s p l e n o m e g a l y Cardiovascular:
h y p e r te n s i o n , h y p o te n s i o n , s y n c o p e Central & Peripheral Nervous: d i z z i n e s s , h e a d a c h e , u p p e r m o t o r n e u r o n l e s i o n
C o l l a g e n . 'l u p u s e r y th e m a to s u s s y n d r o m e , r h e u m a to i d n o d u l e s Ear and Hearing: c e r u m l n o s i s G a s fr a / n te s l m a / ; a b d o m -
i n a l p a i n , C r o h n 's d is e a s e , d i a r r h e a , g a s tr i c u lc e r, i n te s ti n a l o b s tr u c ti o n , I n te s ti n a l p e r fo r a ti o n , i n te s ti n a l s te n o s i s , n a u -
s e a , p a n c r e a ti ti s , p r o c ta l g i a , v o m i ti n g Heart Rate and Rhythm: p a l p i ta ti o n , ta c h y c a r d i a Liver and Biliary: c h o l e c y s ti ti s
Metabolic and Nutritional: d e h y d r a ti o n , p a n c r e a ti c i n s u ffi c i e n c y , w e i g h t d e c r e a s e M u s c o fo s te / e i a / : a r th r o p a th y , b a c k
p a i n , b o n e fr a c tu r e , m y a l g i a , te n d o n d i s o r d e r , te n d o n i n j u r y Myo-, Endo-, Pericardial and Coronary Valve: c a r d i a c fa i l -
u re , m y o c a r d i a l i s c h e m i a Neoplasms: l y m p h o m a Platelet, Bleeding and Clotting: th r o m b o c y to p e n i a Psychiatric: a n x i -
e ty, c o n fu s i o n , d e l i r i u m , d e p r e s s i o n , s o m n o l e n c e , s u i c i d e a tte m p t Red Blood Cell: a n e m i a Resistance Mechanism:
a b s c e s s , c e l l u l i ti s , fe ve r, i n fe c ti o n b a c te r i a l , s e p s i s Respiratory: a d u l t r e s p i r a to r y d i s tr e s s s y n d r o m e , b r o n c h i ti s ,
c o u g h i n g , d y s p n e a , p l e u r i s y , p n e u m o n i a , p u l m o n a r y i n fi l tr a ti o n , r e s p i r a to r y i n s u ffi c i e n c y Skin andAppendages:\um-
c u l o s i s , r a s h , i n c r e a s e d s w e a ti n g i / r i r a / y : a z o te mi a , d y s u r i a , h y d r o n e p h r o s i s , k i d n e y i n fa r c ti o n , re n a l fa i l u r e , u r e te r a l
o b s tr u c ti o n Vascular (Extracariiac): b r a i n i n fa r c ti o n , p u l m o n a r y e m b o l i s m , t h r o m b o p h l e b i t i s d e e p White cell and
M i t a M e f t i f : l e u k o p e n i a , l y m p h a d e n o p a th y A g re a te r p r o p o r t i o n o f p a ti e n ts e n r o l l e d i n to th e A T T R A C T tr i a l w h o
re c e i v e d R E M I C A D E p l u s M T X e x p e r i e n c e d m i l d , tr a n s i e n t e l e v a ti o n s ( <2 ti m e s th e u p p e r l i m i t o f n o r m a l ) In A S T o r
A L T ( 3 7 % e a c h ) c o m p a r e d to p a ti e n ts tr e a te d w i t h p l a c e b o p l u s M T X (A S T : 2 4 %, A L T : 2 9 %) . Five ( 1 . 5 %) p a ti e n ts tr e a t-
e d w i th R E M I C A D E a n d M T X e x p e r i e n c e d m o r e p r o l o n g e d e l e v a ti o n s in th e i r A L T .
O V E R D O S A G E : S i n g l e d o s e s up t o 2 0 m g / k g h a ve b e e n a d m i n i s te r e d w i t h o u t a n y d i r e c t to x i c e ffe c t. I n c a s e o f o v e r -
d o s a g e , i t is r e c o m m e n d e d th a t th e p a ti e n t be m o n i to r e d fo r a n y s i g n s o r s y m p t o m s o f a d v e r s e r e a c ti o n s o r e ffe c ts
a n d a p p r o p r i a te s y m p t o m a t i c tr e a tm e n t I n s ti tu te d i m m e d i a te l y .
S t o r a g e S to r e th e l y o p h i l i z e d p r o d u c t u n d e r r e fr i g e r a ti o n a t 2 C t o 8C ( 3 6 F t o 4 6 F) . D o n o t fr e e z e . D o n o t u s e
b e y o n d th e e x p i r a ti o n d a te . T h i s p r o d u c t c o n ta i n s n o p r e s e r v a ti v e .
H O W S U P P L I E D : R E M I C A D E l y o p h i l i z e d c o n c e n tr a te fo r I V i n j e c ti o n is s u p p l i e d I n i n d i v i d u a l l y - b o x e d s i n g l e - u s e v i a l s
i n th e fo l l o w i n g s tr e n g th :
N D C 5 7 89 4 - 0 3 0 - 0 1 1 0 0 m g i n fl i x i m a b in a 2 0 - m L v i a l
R E F E R E N C E S :
1 . G r e e n s te i n A J , M u l l l n G E , S tr a u c h e n J A , H e i m a n n T , e t a l . L y m p h o m a i n i n fl a m m a t o r y b o w e l d i s e a s e . Cancer
1 9 9 2 ; 6 9 : 1 1 1 9 - 2 1 .
2 . J o n e s M , S y m m o n s D, Finn J , W o l fe F. D o e s e x p o s u r e to i m m u n o s u p p r e s s i v e th e r a p y i n c r e a s e th e 1 0 y e a r
m a l i g n a n c y a n d m o r ta l i ty r i s k s i n r h e u m a to i d a r th r i ti s ? A m a tc h e d c o h o r t s tu d y . Br J Rheum 1 9 9 6 ; 3 5 : 7 3 8- 4 5 .
C e n to c o r , I n c . , M a l v e r n , P A 1 9 3 5 5 , U S A
1 - 80 0 - 4 5 7 - 6 3 9 9
) C e n t o c o r , I n c . 1 999 IN99077 7/00
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