Cleveland Clinic Journal of Medicine 2000 880 2

8/11/2019 Cleveland Clinic Journal of Medicine 2000 880 2

1/5

T A K E - H O M E

P O I N T S F R O M

L ECTURES BY

C L E V E L A N D C L I N I C

A N D V I S I T I N G

FACUL TY

MEDICAL GRAND ROUNDS WILL IAM

5

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Andropause testosterone therapy

and quality of

lif

in aging men

Hypogonadism

may a f fec t

5 mi l l ion men

in th e US

J O H N E . M O R L E Y , M B , B CH *

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

A B S T R A C T

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 man ly voice,

Turning again toward childish treble, pipes

And whistles in his sound...

(Wil l iam Shakespeare , As

You Like It)

F T H E S E S Y M P T O M S m u s c l e

wasting,

regression of secondary sexual charac-

teristics, a r ising 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 f i z e r .

The common wisdom that men do not

undergo menopause is being replaced: many

aging menperhaps 5 mil l ion in the United

Statesdo exper ience androgen def ic ienc ies

that impair quality of life. For these men,

te s to s te r o ne r e p l a c e m e nt the r a p y m a y

improve libido, muscle mass, bone mass, cog-

nition, and energy levels.

N A T U R A L H I S T O RY O F T E S T O S T E R O N E

After age 30, levels of total and bioavailable

testosterone in men decrease by 1% to 2%

per year.

1

This decrease may be caused in

par t by decreased testosterone product ion

and in part by slowly rising levels of sex hor-

m o ne - b i nd i ng g l o b u l i n , the p r o te i n tha t

b inds testosterone and rem oves i t from c ircu-

lat ion. Levels of lu te iniz ing hormone, which

also affects testosterone bioavailability, do

not r ise 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 D E N T I F Y I N G T E S T O S T E R O N E D E F I C I E N C Y

And ropause can be def ined as a comp lex of

androgen-related symptoms that occur in the

presence of low levels of testosterone .2

Symptoms include:

Decreased muscle mass or strength

Cogn it ive changes

Increase d fat mass, particularly visceral fat

Osteoporosis

Low sense of well-being

Decreased sexual desire and impaired sex-

ual function

Mo od change s, including depression, irri-

tability, loss of motivation, and lethargy

8 8 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 NUMBER 2 DECEMBER 20 00

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W e l C h o l (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

year. However, caution should be exercised when treating patients with a susceptibility to vitamin K or fat soluble vitamin deficiencies.

Wel C ho l 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 f e 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 is t ic 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 f o 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) T A B L E T S

R x o n l y

Brief Sum mary see package insert for ful l prescribing information.

I N D I C A T I O N S A N D U S A G E

WelChol, administered alone or in combination with an HMG-CoA reductase

inhibitor, is indicated as adjunctive therapy to diet and exercise for the reduc-

t ion of elevated LDL cholesterol in pat ients with primary hypercholesterolemia

(Fredrickson Type lla).

C O N T R A I N D I C A T I O N S

WelChol is contraindicated in individuals with bow el obstruct ion and in individ-

uals who have shown hypersensit ivity to any of the components of WelChol.

P R E C A U T I O N S

G e n e r a l : Patients with TG levels greater than 300 mg/dL were excluded from

WelChol cl inical tr ia ls. Caution should be exercised wh en treat ing pat ients with

TG levels greater than 300 mg/dL.

In non-clinical safety studies, rats administered with colese velam at dos es greater

than 30-fold the p rojected human clin ical dose experienced hem orrhage from vit-

amin K deficiency. WelChol did not induce any clinically significant reduction in

the absorption of vitamins A, D, E, or K during clinical trials of up to one year.

However, caution should be exercised when treating patients with a susceptibil-

ity to vitamin K or fat soluble vitamin deficiencies.

The safety and eff icacy of WelChol in pat ients with dysphagia, s wallowing dis-

orders, severe gastrointest inal moti l i ty disorders, or major gastrointest inal tract

surgery have not been established. Consequently, caution should be exer-

cised when WelChol is used in pat ients with these gastrointest inal disorders.

I n f o r m a t i o n f o r t h e P a t i en t :WelChol may be taken once per day with a meal,

or taken twice per day in divided doses with meals. Patients should be direct-

ed to take WelChol with a l iquid and a meal, and adhere to their NCEP-rec-

ommended diet. Patients should tell their physicians if they are pregnant, are

intending to become pregnant, or are breast-feeding.

L a b o r a t o r y T e s t s :S erum total-C, LDL -C, and TG levels should be determined

periodically based on NCEP guidelines to confirm favorable init ia l and ade-

quate long-term responses.

D r u g I n t e r a c t i o n s : WelChol has been studied in several human drug interac-

t ion studies in which it was administered with a meal and the test drug.

WelC hol was found to have no signif icant effect on the bioavailabil ity of digox-

in, lovastatin, metoprolol, quinidine, valproic acid, and warfarin. WelChol

decreased the Cmax and AUC of sus tained-release verapamil by approxim ate-

ly

3 1

% and 11%, respectively. Since there is a high degree of variability in the

bioavailability of verapamil, the clinical significance of this finding is unclear. In

clin ical studies, co-administrat ion of WelChol with atorvastat in, lovastat in, or

simvastat in did not interfere with the l ip id-lowering act ivity of the HMG-CoA

reductase inhibitor. Other drugs have not been studied. When administering

other drugs for which alterations in blood levels could have a clinically signifi-

cant effect on safety or eff icacy, physicians should consider monitoring drug

levels or effects.

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 , I m p a i r m e n t o f F e rt i l i t y

A 104-week carcinogenicity study with colesevelam (WelChol) was conducted

in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approxi-

mate ly 50 t imes the maximum recommended human dose o f

4.5 g/day, based on body weight, mg/kg. There were no signif icant drug-

induced tumor f indings in male or female mice. In a 104-week carcinogenicity

study with colesevelam (WelChol) in Harlan Sprague-Dawley rats, a statistically

significant increase in the incidence of pancreatic acinar cell adenoma was seen

in male rats at doses >1.2 g/kg/day (approximately 20 t imes the maximum

human dose, based on body weight, mg/kg) (trend test only). A statistically sig-

nificant increase in thyroid C-cell adenoma was seen in female rats at 2.4

g/kg/day (approximately 40 t imes the maximum human dose, based on body

weight, mg/kg).

Colesevelam and four degradants present in the drug substance have been

evaluated for mutagenicity in the Ames test and a mamm alian chro mos oma l

aberrat ion test. The four degradants and an extract of the parent compound

did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in

S. typhimurium and coli (Ame s assay) wit h or with out rat liver me tabolic a cti-

vat ion. An extract of the parent compound was posit ive in the Chinese

Hamster Ovary (CHO) cell chromosomal aberrat ion assay in the presence of

metabolic act ivat ion and negative in the absence of metabolic act ivat ion. The

results of the CHO cell chromosomal aberrat ion assay with two of the four

degradants, decylamine HCI and aminohexyltrimethyl ammonium chloride HCI,

were equivocal in the absence of metabolic act ivat ion and negative in the pres-

ence of metabolic act ivat ion. The other two degradants, didecylamine HCI and

6-decylamino-hexyltrimethyl ammonium chloride HCI, were negative in the

presence and absence of metabolic act ivat ion.

Colesevelam did not impair fert il i ty in rats at doses of up to 3 g/k g/day (approx-

imately 50 t imes the maximum human dose, based on body weight, mg/kg).

P R E G N A N C Y

P r e g n a n c y C a t e g o r y B : Reproduction studies have been performed in rats

and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approxi-

mately 50 and 17 t imes the maximum human dose, based on body weight,

mg/kg), and have revealed no evidence of harm to the fetus due to coleseve-

lam. There are, however, no adequate and well-controlled studies in pregnant

women. Because animal reproduction studies are not always predict ive of

human response, this drug should be used during pregnancy only if clearly

needed. Requirements for vitamins and other nutrients are increased in preg-

nancy. The effect of WelChol on the ab sorpt ion of vitamins has not b een stud-

ied in pregnant women.

P e d i a t r i c U s e : The safety and efficacy of colesevelam (WelChol) have not

been established in pediatric pat ients.

G e r i a t r i c U s e : There is no evidence for special considerat ions when cole-

sevelam (WelChol) is administered to elderly patients.

A D V E R S E R E A C T I O N S

WelCho l t rea tment -emergent adverse events tha t occurred in g reater

than 2 % of pat ients in an integrated safety analysis are presented in the table

below.

F r e q u e n t ( > 2 ) T r e a t m e n t - E m e r g e n t A d v e r s e E v e n t s B y T r e a t m e n t

C a t e g o r y

B O D Y S Y S T E M / P l a c e b o W E L C H O L O N L Y

A D V E R S E E V E N T

( N = 2 5 8 )

( N = 8 0 7 )

B o d y a s a W h o l e

Infect ion 13 10

Headache 8 6

Pain

7

5

Back Pain 6 3

Abdomina l Pa in

5 5

Flu Syndrom e

3 3

Accide ntal Injury 3

4

Asthenia

2 4

D i g e s t i v e S y s t e m

Flatulence

14 12

Constipat ion 7 11

Diarrhea

7 5

Nausea

4 4

Dyspepsia

3 8

R e s p i r a t o r y S y s t e m

Sinusitis 4 2

Rhinitis 3 3

Cough Increased 2 2

Pharyngit is

2 3

M u s c u l o s k e l e t a l S y s t e m

Myalgia 0

2

O V E R D O S A G E

Because We lChol is not absorbed, the risk of systemic toxicity is low. Doses in

excess of 4.5 g per day have not been tested.

D O S A G E A N D A D M I N I S T R A T I O N

M o n o t h e r a p y : The recommended start ing dose of WelChol is 3 tablets taken

twice per day with meals or 6 tablets once per day with a meal. The WelChol

dose can be increased to 7 tablets, depending upon the desired therapeutic

effect. WelChol should be taken with a l iquid.

C o m b i n a t i o n T h e r a p y :WelChol, at doses of 4 to 6 tablets per day, has been

shown to be safe and effect ive when dosed at the same t ime (i.e., co-admin-

istered) as an HMG-CoA reductase inhibitor or when the two drugs are dosed

apart. WelChol should be taken with a l iquid. For maximal therapeu tic effect in

combination with an HMG-CoA reductase inhibitor, the recommended dose of

WelChol is 3 tablets taken twice per day with m eals or 6 tablets taken once per

day with a meal.

H O W S U P P L I E D :

WelChol is supplied as an off-white, f i lm-coated solid tablet imprinted with the

wo rd Sankyo over C 01, con taining 625 mg colesevelam.

Marketed for: Sankyo Ptiarma Inc., NEW York, NY 10017

Marketed by: Sankyo Parke Davis, Parsippany, NJ 07054

P H A R M A

SPWCOO-0016

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Regression of secondary sexual character-

istics

Impaired sperm prod uctio n.

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 D A M ) Q u e st i o nna i re , to g e the r w i th a

complete history and physical examination, is

useful in identifying patients who may benefit

from testing for hypogonadism

(

TABLE

1 ) .

6

O T H E R C A US ES O F H Y P O G O N A D I S M

Age is not the only cause of hypogonadism,

which has an estimated prevalence of 4 to 5

mil l ion men.

7

Other causes include primary

testicular failure (either congenital , develop-

mental, or acquired),

8

obesity, severe systemic

il lnesses, malnutrition, AIDS, uremia, sickle

cell disease, or hepatic cirrhosis.4

T E S T I N G F OR T E S T O S T E R O N E

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-b inding

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 bot h free testo stero ne and p rotein -

bound testosterone.

3

This test can produce

normal readings even when age-re lated

increases in sex hormone-binding globulin

lower concentrations of bioavailable testos-

terone. In addition, the test may have false-

posi t iv e resul ts in insul in-resista nt men ,

because excess insulin lowers the concentra-

tion of sex horm one-bind ing globulin, w hich

can lower total testosterone levels even when

T A B L E 1

T h e A D A M q u e s t i o n n a i r e

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.

And ro ge n Deficiency in Agin g Mal es

bioavailable testosterone is adequate.

Another option is the calculated f ree

testosterone index. This has been validated in

a recent study.

9

H e a l thy m e n e x p e r i e nc e w i d e ho u r - to -

hour and day- to-day f luc tuat ions in testos-

terone levels (up to 20% over the course of

a w e e k ) , so sy m p to m a t i c m e n w i th no r m a l

test results should be tested more than

o nc e .

I f any of these tests conf irm testos-

teron e def ic iency , tests of gon ado trop in lev-

e ls wi l l he lp determine whether the cause of

the hy p o g o na d i sm i s p r i m a r y ( hy p e r -

g o na d o tr o p i c hy p o g o na d i sm ) o r se c o nd a r y

t o p i t u i t a r y d i s e as e ( h y p o g o n a d o t r o p i c

hy p o g o na d i sm ) . I n the l a t te r c o nd i t i o n ,

gonadotropins fail to r ise in response to low

testosterone levels .

Serum prolactin levels should also be

measured to screen for hyperprolactinemia.

This can be caused by heart or renal failure,

hypothyroidism, or a number of drugs.

T E S T O S T E R O N E T H E R A P Y

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 bioavai lable

testosterone

assay is

the tes t o f

choice fo r

o lder men

880 CLEVE LAND CL INIC JOUR NAL OF MEDI CINE VOL UME 67 NUMB ER 1 2 DECEM BER 20 00

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M E D I C A L G R A N D R O U N D S

b o n e 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,

in tramuscular in ject ions , t ransdermal patch-

es , and transdermal gel .4 Unfortunately ,

in tramuscular in ject ions can produce widely

f luctuat ing serum testosterone levels .

1 1

T h e

transdermal patch, although it provides more

physiologic testosterone levels, may cause

rashes .

1 2

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

p a t c h .

1 3

Using testosterone gel may also min-

imize skin reactions.

Both testosterone gel and the patch were

associated with improved l ibido 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 o f tes tosterone

therapy are increased upper body strength,

improved l ipid balance, better memory, beard

growth, and coronary artery vasodilation. In a

mouse model of Alzh eime r disease, testos-

terone reversed memory deficits by inhibit ing

overpr oduct ion o f amylo id precursor pro-

tein. '4 Testosterone may be beneficial for car-

diovascular risk factors and for benign prosta-

t i c hyperplas ia .

5

'

1 5

-

1 7

Testosterone may increase the hematocr i t

and the risk of strokes. Testo steron e therapy is

not indicated for men with prostatic cancer,

but there is no evid enc e tha t tes tosteron e

increases th e risk of prostate can cer.

R E F E R E N C E S

Elevated

pro lac t in

can be due

to h eart or

renal fa i lure,

hypothyro id ism,

or a number

of drugs

1 . M o r l e y J E , K a i s e r F E , 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 in 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 in

h e a l t h y o l d e r m e n . M e t a b C l in E x p e r 1 9 9 7 ;

4 6 : 4 1 0 - 4 1 3 .

2 . M o r l e y JE , P e r r y H M 3 r d . A n d r o g e n d e f i c i e n c y i n

a g i n g m e n : r o le 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 in

N o r t h A m 1 9 9 8 ; 2 7 : 9 6 9 - 9 8 7 .

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 as k F o 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 se 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 JE .

T e s t o s t e r o n e a n d l e p t i n in 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 8 5 - 1 0 9 1 .

6 . M o r l e y JE , 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 f i 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 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 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 it 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 F a 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

f r 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 ; 8 4 : 3 6 6 6 - 3 6 7 2 .

1 0 . S i h R, M o r l e y JE , K a i s e r F E , P e r r y H M 3 r d , P a t r i c k P ,

R o ss 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 ri o n th 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 ; 8 2 : 1 6 6 1 - 1 6 6 7 .

1 1 . B e h r e H M , N e i s c h la 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 f i c i e n c y , S u b s t i t u t i o n . B e r l in , 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 ys i c ia n s ' D e s k

R e f e 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 en : 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 es : 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 in E n d o c r i n o l M e t a b 2 0 0 0 ;

8 5 : 9 6 4 - 9 6 9 .

1 4 . F l o o d J F, F a r r S A, K a i s e r F E , 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 re 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 ys 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 in 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 RR , K a i s e r F E, 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 in 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 99 7 ; 8 2 : 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 is -

e a s e . C h i n M e d Sc 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

CLEVE LAND CLINIC JOURNAL OF MEDICI NE VOL UME 67 NUMBER 12 DECEMBER 20 00

http://www.aace.com/clin/guides/http://www.fda.gov/http://www.ccjm.org/http://www.ccjm.org/http://www.ccjm.org/http://www.fda.gov/http://www.aace.com/clin/guides/


5/5

REMICADE

( i n f l i x i m a b )

f o r IV 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 f o r f u l l p r e s c r i b i n g i n f o 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 t o 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 t i o n w i t h m e t h o t r e x a te ,

is

i n d i c a t e d f o r t h e

r e d u c t i o n I n s i g n s a n d s y m p t o m s o f r h e u m a t o i d a r th r i ti s i n p a t ie n t s w h o h a v e h a d a n i n a d e q u a t e r e s p o n s e t o m e t h o t r e x -

a t e . C r o h n ' s D i s e a s e R E M I C A D E i s i n d i c a t e d f o r t h e r e d u c t i o n i n 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 i s e a s e i n p a t i e n t s w i t h

m o d e r a t e l y t o s e v e r e l y a c t iv e C r o h n ' s d i s e a s e w h o h a v e h a d a n In a d e q u a t e r e s p o n s e t o c o n v e n t i o n a l t h 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 in d i c a t e d f o r

t h e r e d u c t i o n in t h e n u m b e r o f d r a i n i n g e n t e r o c u t a n e o u s f i s t u l a e i n p a t i e n t s w i t h f i s t u 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 t e r e d t o p a ti e n t s w i t h k n o w n h y p e r s e n s i t iv i t y to a n y m u r i n e

p r o t e i n s o r o t h 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 TA 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 FT 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 C H R O N I C

I N F E C T I O N O R 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

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

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

P A T I E N T D E V E L O P S

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 t e d w i t h h y p e r s e n s i t i v i ty r e a c t i o n s t h a t v a r y i n t h 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 t i v i ty r e a c t io n s , w h i c h i n c l u d e u r t i c a r ia , d y s p n e a a n d / o r h y p o t e n s i o n , h a v e o c c u r r e d d u r i n g o r w i t h i n2

h o u r s o f i n f l i x i m a b i n f u 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 ik e r e a c t i o n s h a v e b e e n o b s e r v e d I n C r o h n ' s

d i s e a s e p a t i e n t s

3 t o

1 2 d a y s a f t e r R E M I C A D E t h e r a p y w a s r e i n s t lt u t e d f o l l o w i n g

an

e x t e n d e d p e r i o d w i t h o u t

R E M I C A D E t r e a t m e n t . S y m p t o m s a s s o c i a t e d w i t h t h e s e r e a c t io n s i n c l u d e l e v e r , ra s h , h e a d a c h e , s o r e t h ro 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 f a 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 t i o n s w e r e a s s o c i a t e d w i t h m a r k e d i n c r e a s e

i n a n t i b o d i e s t o i n f l ix i m a b , l o s s o f d e t e c t a b l e s e r u m c o n c e n t r a t io 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 f fi c a -

c y . R E M I C A D E s h o u l d b e d i s c o n t i n u e d f o r s e v e r e r e a c t io n s . M e d i c a t i o n s f o r th e t r e a t m e n t o f h y p e r s e n s i t iv i t y r e a c -

t i o n s ( e . g . , a c e t a m i n o p h e n , a n t i h i s t a m i n e s , c o r t i c o s t e 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 b e a v a i la b l e f o r i m m e d i a t e u s e

I n th e e v e n t o fa r e a c t i 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 t m e 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 f o r m a t i o n o f a u t o a n t ib o d i e s a n d , r a r e ly ,

i n t h e d e v e l o p m e n t o f a lu p u s - l i k e s y n d r o m e . I f a p a t i 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 t i v e o f a l u p u s - l ik e s y n d r o m e

f o 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 re a t m e n t s h o u l d

be

d i s c o n t i n u e d

(see ADVERSE REACTIONS,

Autoantibodies/Lupus-like Syndrome).

M a l i g n a n c y P a t ie n t s w i t h l o n g d u r a t i o n

o f

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 ti s a n d c h r o n i c e x p o s u r e to i m m u n o s u p p r e s s a n t t h 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, MalignanciesAymphoprollferativeDisease . T h e i m p a c t oft r e a t m e n t w i t h R E M I C A D E o n

t h e se 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 t m 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 ia t e d w i t h th e d e v e l o p m e n t

o f a n t ib o d i e s t o i n f li x i m a b ( a l s o r e f e rr e d t o a s h u m a n a n t l c h i m e r i c a n t i 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 - f o u r o f

t h e 1 9 9 C r o h n ' s d i s e a s e p a t i e n ts t re a t e d w i t h R E M I C A D E w e r e e v a l u a t e d f o r th e d e v e l o p m e n t o f i n f l i x im a b - s p e c i f ic

a n t i b o d i e s ; 1 8 ( 1 3 % ) w e r e a n t i b o d y - p o s i t i v e ( t h e m a j o r i ty a t l o w l i te r , < 1 : 2 0 ) . P a t ie n t s w h o w e r e a n t i b o d y - p o s i t i 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

an

i n f u s i o n r e a c t i o n ( s e e ADVERSE REACTIONS, Intusm-related Reactions .

A n t i 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 t o i d a r t h r i ti s a n d C r o h n 's d i s e a s e p a t i 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 t h 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 t h r e p e a t e d d o s i n g

of

R E M I C A D E , s e r u m c o n c e n t ra t io n s

o f

i n f l ix i m a b w e r e h i g h e r I n rh e u m a t o i d a r t h r it i s p a ti e n t s w h o r e c e i v e d c o n c o m i t a n t M T X T h e r e a r e l im i t e d d a t a a v a i l-

a b l e o n th e d e v e l o p m e n t ofa n t i b o d i e s to in f l i x i m a b in p a t i e n t s r e c e i v in g l o n g - t e r m t r e a t m 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 r e p r o d u c t - s p e c i f i c , c o m p a r i s o n o l a n t i b o d y r a t e s t o t h o s e f r o m o t h e r p r o d u c t s

i s n o t a p p r o p r i a t e .

V a c c i n a t i o n s

N o d a t a a r e a v a i la b l e o n t h e r e s p o n s e t o v a c c i n a t i o n o r o n t h e s e c o n d a r y t r a n s m i s -

s i o n o f i n f e c t i o n b y l i v e v a c c i n e s i n p a t i e n t s re c e i v i n g a n t i - T N F t h e r a p y .

It

Is r e c o m m e n d e d t h a t l i ve v a c c i n e s n o t b e

g i v e n c o n c u r r e n t l y . D r u g I n t e r a c t i o n s S p e c i f ic d r u g i n t e r a c t i o n s t u d i e s , i n c l u d i n g I n t e r a c t i o n s w i t h M T X , h a v e n o t

b e e n c o n d u c t e d . T h e m a j o r i t y ofp a t i 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 o r C r o h n ' s d i s e a s e c l i n i c a l t ri a l s r e c e i v e d o n e or

m o r e c o n c o m i t a n t m e d i c a t i o n s . In r h e u m a t o i d a r t h r it i s , c o n c o m i t a n t m e d i c a t i o n s b e s i d e s M T X w e r e n o n s t e r o id a l

a n t i - i n f la m m a t o r y a g e n t s , f o l ic a c i d , c o r ti c o s t e r o i d s a n d / o r n a r c o t i c s . C o n c o m i t a n t C r o h n ' s d is e a s e m e d i c a t i o n s w e r e

a n t i b i o t ic s , a n t i v i ra l s , c o r t i 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 la t e s . P a t i e n t s w i t h C r o h n ' s d i s e a s e w h o r e c e iv e d

I m m u n o s u p p r e s s a n t s t e n d e d t o e x p e r i e n c e fe w e r i n f u s i o n r e a c ti o n s c o m p a r e d

to

p a ti e n t s o n n o i m m u n o s u p p r e s -

s a n t s (seePRECAUTIONS, Immunogenici ty

a n d

ADVER SE REACTION S, 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 t u d i e s i n

a n i m a l s

h a v e n o t b e e n p e r f o r m e d

t o e v a l u a t e th e c a r c i n o g e n i c p o t e n t ia l . N o c l a s t o g e n i c o r m u t a g e n i c e f fe c t s o f I n f li x i m a b w e r e o b s e r v e d i n t h e

in vivo

m o u s e m i c r o n u c l e u s t e s t o r t h e

Salmonella-Escherichiacoii

( A m e s ) a s s a y , re s p e c t i v e ly . C h r o m o s o m a l a b e r r a t io n s

w e r e n o t o b s e r v e d I n a n a s s a y p e r f o r m e d u s i n g h u m a n l y m p h o c y t e s . I t i s n o t k n o w n w h e t h e r i n f l i x i m a b c a n i m p a i r

f e r t i l i t y in h u m a n s . N o i m p a i r m e n t o f f e r ti l it y w a s o b s e r v e d i n a f e r ti l it y a n d g e n e r a l r e p r o d u c t i o n t o x i c i t y s t u d y c o n -

d u c t e 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 t i b o d y t h a t s e l e c ti v e ly i n h i b i t s t h e f u n c t i o n a l a c t iv i ty o f m o u s e T N F a ,

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 f l ix i m a b d o e s n o t c r o s s - re a c t w i t h T N F a I n s p e c ie s o t h e r t h 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 t i o n s t u d i e s h a v e n o t b e e n c o n d u c t e 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 t h e r R E M I C A D E c a n c a u s e f e t a l

h a r m w h e n a d m i n i s t e r e d t o a p r e g n a n t w o m a n o r c a n a f f e c t re p r o d u c t i o n c a p a c i t y w h i l e i n fl i x im a b i s p r e s e n t in t h e

s e r u m . R E M I C A D E s h o u l d b e g iv e n t oa p re g n a n t w o m a n o n l y if c l e a r l y n e e d e d . N o e v i d e n c e ofm a t e r n a l t o x i c i t y ,

e m b r y o t o x i c i t y o r t e r a to g e n i c i t y w a s o b s e r v e d i n a d e v e l o p m e n t a l t o x i c i t y s tu d y c o n d u c t e 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 t i b o d y t h a t s e l e c t i v e l y i n h i b i t s t h e f u n c t i o n a l a c t i v i t y

of

m o u s e T N F a .

N u r s i n g M o t h e r s It is

n ot k n o w n

w h e t h e r I n f l i x i m a b

is

e x c r e t e d

in

h u m a n m i l k o r a b s o r b e d s y s t e m l c a l l y a f te r i n g e s t io 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 r e 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 t h e p o t e n t i a l f o r a d v e r s e r e a c t io n s i n n u r s i n g i n f a n t s

f r o m R E M I C A D E , a d e c i s io n s h o u l d b e m a d e w h e t h e r t o d i s c o n t i n u e n u r s i n g o r to d i s c o n t i n u e t h e d r u g , ta k i n g i n t o

a c c o u n t t h e I m p o r t a n c e o f t h e d r u g t o t h e m o t h e r .

P e d i a t r i c

U s e S a f e t y a n d e f f e c t iv e n e s s o f R E M I C A D E i n p a t i e n t s

w i t h j u v e n i l e r h e u m a t o i d a r t h r i ti s a n d i n p e d i a t r ic p a t i e n t s w i t h C r o h n ' s d i se a s e h a v e n o t b e e n e s t a b l is 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 t u d y , n o o v e r a l l d i f f e r e n c e s w e r e o b s e r v e d i n e f f e c t i v e n e s s o r s a f e t y In t h e 7 2 p a t i e n t s 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 t i e n t s . In C r o h n ' s d i s e a s e s t u d i e s , th e r e w e r e i n s u f f i c i e n t n u m b e r s o f p a t i e n t s a g e d

6 5 o r o l d e r t o d e t e r m i n e w h e t h e r t h e y r e s p o n d d i f fe r e n t l y f ro m p a t i e n ts a g e d 1 8 t o 6 5 . B e c a u s e t h e r e i sa h i g h e r

i n c i d e n c e

of

i n f e c t i o n s

in

th e e l d e r ly p o p u l a t i o n

in

g e n e r a l , c a u t i o n s h o u l d b e u s e d

in

t r e a t i n g t h 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 t o t a l o f 7 7 1 p a t i e n t s w e r e t r e a t e d w i t h R E M I C A D E I n c l i n i c a l t r i a l s .

In

b o t h r h e u m a t o i d

a r t h r i ti s a n d C r o h n ' s d i s e a s e t r i a l s , a p p r o x i m a t e l y 5 % of p a t i e n t s d i s c o n t i n u e d R E M I C A D E b e c a u s e of 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 f o r d i s c o n t i n u a t i o n o f tr e a t m e n t w e r e d y s p n e a , u r t ic 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 f u s i o n r e a c ti o n w a s d e f i n e d a s a n y a d v e r s e e v e n t o c c u r r i n g

d u r i n g t h e I n f u s i o n o r w i t h i n 1

t o 2

h o u r s a f t e r t h e I n f u s io n . S e v e n t e e n p e r c e n t o f R E M I C A D E - t re a t e d p a t i e n t s

in

a l l 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 f u s i o n r e a c t i o n c o m p a r e d

to

7 % ofp l a c e b o - t r e a te d p a t i e n ts . A m o n g t h e 3 2 8 4

R E M I C A D E i n f u 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 f ic s y m p t o m s s u c h a s fe v e r o r c h i l ls , 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 t ic 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 t io n s ( p r i m a r i l y c h e s t p a i n , h y p o t e n s i o n ,

h y p e r t e 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 t u s /u r t i c a r ia a n d c a r d i o p u l -

m o n a r y r e a c t i o n s . L e s s t h a n 2 % o f p a t i e n t s d i s c o n t in u e d R E M I C A D E b e c a u s e o f i n f u s i o n r e a c t io n s , a n d a l l p a t ie n t s

r e c o v e r e d w i t h t r e a t m e n t a n d / o r d i s c o n t i n u a t i o n of i n f u s i o n . R E M I C A D E i n f u s i o n s b e y o n d t h e i n i t i a l in f u s i o ni n

r h e u m a t o i d a r t h r i ti s p a t i e n t s w e r e n o t a s s o c i a t e d w i t h a h i g h e r I n c i d e n c e o f r e a c t i o n s . P a t ie n t s w i t h 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 t i v e f o r a n ti b o d i e s t o in f l i x im a b w e r e m o r e l i k e ly t o d e v e l o p i n f u s i o n r e a c t io n s t h a n w e r e t h o s e w h o

w e r e n e g a t i v e ( 3 6 % v s . 1 1 % r e s p e c t i 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 t s a p p e a r e d t o re d u c e t h e

f r e q u e n c y of a n t i b o d i e s to i n f l i x i m a b a n d i n f u s i o n r e a c t i o n s ( s e e

PRECAUTIONS,

Immunogenicity a n d Drug

Interactions). Reactions following readministration In a c l i n i c a l tr i a l o f f o r t y p a t i e n t s w i t h C r o h n ' s d i s e a s e r e t r e a t e d

w i t h i n f l i x i m a b f o l l o w i n g a 2 to 4 y e a r p e r i o d w i t h o u t i n f l i x i m a b t r e a t m e n t , 1 0 p a t i 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 t s

m a n i f e s t in g 3 t o 1 2 d a y s f o l lo w i n g I n f u 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 t h 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 t i e n ts a l s o e x p e r i e n c i n g p r u r i t u s , la 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 t ic 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 t i e n ts e x p e r i e n c i n g t h e s e a d v e r s e e v e n t s h a d n o t e x p e r i e n c e d i n f u -

s i o n - r e l a t e d a d v e r s e e v e n t s a s s o c i a t e d w i t h th e i r i n i t i a l i n f l i x i m a b t h e r a p y . O f t h e 4 0 p a t i e n t s e n r o l l e d , t h e s e a d v e r s e

e v e n t s o c c u r r e d i n 9 o f 2 3 ( 3 9 % ) w h o h a d r e c e iv e d l i q u i d f o r m u l a t i o n w h i c h i s n o 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 lz e d f o r m u l a t i o n . T h e c l i n i c a l d a ta a r e n o t a d e q u a t e t o d e t e r m i n e i f o c c u r r e n c e o f t h e s e r e a c t io n s

i s d u e t o d i f fe r e n c e s i n f o r m u l a t i o n . P a t i e n t s ' 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 t a n t i a l l y o r r e s o l v e d w i t h t r e a t m e n t

i n a l l c a s e s . T h e r e a r e i n s u f f i c i e n t d a t a o n th e i n c i d e n c e o f th e s e e v e n t s a f t e r d r u g - f r e e i n t e r v a l s o l l e s s t h a n 2 y e a r s .

H o w e v e r , t h e s e e v e n t s h a v e b e e n o b s e r v e d i n f r e q u e n t l 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 t e r v a l s

o f l e s s t h a n

1

y e a r . I n f e c t i o n s

In

R E M I C A D E ( i n f l i x i m a b ) c l i n i c a l t ri a l s . I n f e c t i o n s w e r e r e p o r t e d

by

2 6 %

o f

R E M I C A D E - t re a t e d p a t i e n t s ( 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 - t r e a t e d p a t i e n t s ( a v e ra g e o f

2 0 w e e k s o f f o l l o w - u p ) . T h e i n f e c ti o n s m o s t f r e q u e n t l y r e p o r t e d w e r e u p p e r r e s p i r a t o r y t r a c t i n f e c t io n s ( i n c l u d i n g ,

s i n u s i t i s , p h a r y n g i t i s , a n d b r o n c h i t i s ) a n d u r i n a r y tr a c t i n f e c t i 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 f e c t i 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 la c e b o . A m o n g R E M I C A D E - t re a t e d p a t i e n t s , t h e s e s e r i o u s i n f e c t io n s

i n c l u d e d p n e u m o n i a , c e l l u li t is , p y e l o n e p h r i t is a n d s e p s i s . I n th e A T T R A C T s t u d y , o n e p a t ie n t d i e d w i t h d i s s e m i n a t e d

t u b e r c u l o s i s a n d o n e d ie d w i t h d i s s e m i n a t e 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 t io n s h i p t o R E M I C A D E i s u n k n o w n ( s e e

WARNINGS,

Risk ol

Infections .

T w e l v e p e r c e n t o f p a t ie n t s w i t h f i 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 f t e r t h e l a s t i n f u 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 ik e S y n d r o m e P a t i e n t s w e r e te s t e d f o r

a u t o a n t i b o d i e s at m u l t i p l e t i m e p o i n t s . Int h e r h e u m a t o i d a r t h r i t is A T T R A C T s t u d y , 2 3 % o f R E M I C A D E - t r e a t e d

p a t i e n t s d e v e l o p e d a n t in u c l e a r a n t ib o d i e s ( A N A ) b e t w 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 t i o n , c o m p a r e d t o 6 % o f p l a c e b o -

t r e a te d p a t i e n t s . A n t i - d s D N A a n t i 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 t e l y 4 % o f R E M I C A D E - tr e a t e d p a t i e n t s , c o m p a r e d t o

n o n e o f th e p l a c e b o - t r e a te d p a t ie n t s . N o a s s o c i a t i o n w a s s e e n b e t w 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 t l -d s D N A . O f C r o h n ' s d is e a s e p a t i e n t s tr e a t e 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 t e d f o r a n t i n u c l e a r a n t i -

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 t w e e n s c r e e n i n g a n d la s t e v a l u a ti o n . A n t i - d s D N A a n t i 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 t e l y 9 % o l C r o h n ' s d i s e a s e p a t ie n t s tr e a t e d w i t h 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 t i -d s D N A a n t i 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 t h e d o s e o r d u r a ti o n o f R E M I C A D E t r e a t m 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 t ie n t s w a s a s s o c i a t e d w i t h re d u c e d d e v e l o p m e n t o l a n t i -d s D N A a n t i b o d i e s ( 3 %

c o m p a r e d t o 2 1 % i n p a t i e n t s n o t re 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 t ie n t s w e r e a p p r o x i m a t e l y

2 t i m e s m o r e l i k e l y t o d e v e l o p a n t l -d s D N A a n t i b o d i e s

it

t h e y w e r e A N A - p o s l t i v e a t s t u d y e n t i y . T h re e p a t i e n t s 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 t e n t w i t h a l u p u s - l ik e s y n d r o m e , t w o w i t h r h e u m a t o i d a r t h 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 t h r e e p a t i e n ts I m p r o v e d f o l l o w i n g d i s c o n t i n u a t i o n o l t h e r a p y a n d a p p r o p r i a t e m e d i c a l t r e a t m 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 F i v e 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 t ie n t s t re a t e d w i t h R E M I C A D E l o r u p t o 3 6 w e e k s i n c l i n ic a l t r ia 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 ly m p h o m a , b r e a s t ca 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 t h e s k i n , a n d b a s a l c e ll c a n c e r . T h e r e

a r e I n s u f fi c i e n t d a t a t o d e te r m i n e w h e t h e r R E M I C A D E c o n t r i b u t e d t o t h 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 r a te s a n d i n c i d e n c e s w e r e s i m i l a r to t h o s e e x p e c t e d f o r t h e p o p u l a t i 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 t s o c c u r r i n g a t a fr e q u e n c y o f a t l e a s t 5 % i n t r i a l s i n p a t i e n t s

w i t h r h e u m a t o i d a r t h r it i s o r C r o h n ' s d i s e a s e a re s h o w n i n th e t a b l e b e l o w . P a t i e n t s w i t h C r o h n ' s d i s e a s e w h o w e r e

t r 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 ly t h a n p a t i e n ts w i t h r h e u m a t o i d a r t h r i ti s t o e x p e r ie n c e a d v e r s e e v e n t s a s s o -

c i a te d w i t h g a s t r o in t e s t in 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 IS 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 ce 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 f o 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 t o r y

U p p e r r e s p i r a t o r y i n f e 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 t i s 3 %

9 % 2 %

5 %

R h i n i ti s 4 % 8 % 4 % 6 %

P h a r y n g i t i s 5 %

8 %

5 % 9 %

B r o n c h i ti s 2 % 4 % 2 % 7 %

G a s t r o i n t e s t i 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 in g 1 0 % 5 % 0 % 9 %

O t h 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 %

F a t i g u e

5 % 6 % 5 % 1 1 %

F e v er 4 % 6 %

7 %

1 0 %

B a c k p a in 2 % 6 % 4 %

5 %

P a in 4 % 6 % 5 % 9 %

U r i n a r y tr a c t i n f e c t i o n

3 %

6 % 4 %

3 %

P r u r it u 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 t s b y b o d y s y s t e m t h a t o c c u r r e d I n a ll p a t i e n ts t r e a te d w i t h R E M I C A D E a t f r e q u e n c i e s < 2 % a r e

a s f o l l o w s :

Body as a whole:a b d o m i n a l h e r n i a , c h e s t p a i n , f a l l , p a i n Blood: s p l e n i c i n f a r c ti o n , s p l e n o m e g a l yCardiovascular:

h y p e r t e n s i o n , h y p o t e n s i o n , s y n c o p e

Central& PeripheralNervous:

d iz 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 io n

C o l l a g e n . 'l u p u s e r y t h e m a t o s u s s y n d r o m e , r h e u m a t o i d n o d u l e s ar

and Hearing:

c e r u m l n o s i s G a s f r 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 i s e a s e , d i a r rh e a , g a s t r i c u l c e r , i n t e s t i n a l o b s t r u c t i o n , I n t e s t in a l p e r f o r a t i o n , i n t e s t i n a l s t e n o s i s , n a u -

s e a , p a n c r e a t i t i s , p r o c t a l g i a , v o m i t i n g Heart Rateand Rhythm: p a l p i t a t i o n , t a c h y c a r d i a Liverand Biliary: c h o l e c y s t i t i s

Metabolic and Nutritional: d e h y d r a t io n , p a n c r e a t ic i n s u f fi 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 f o s t e / e i a / : a r th r o p a t h y , b a c k

p a i n , b o n e f r a c t u r e , m y a l g i a , t e n d o n d i s o r d e r , t e n d o n i n j u r y

Myo- ,Endo-, Pericardial

an d

CoronaryValve:

c a r d i a c f a i l -

u r e , 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, Bleedinga ndClotting:

t h ro m b o c y t o p e n i a

Psychiatric:

a n x i -

e t y , c o n f u s i o n , d e l i ri 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 t t e m p t Red Blood

Cell:

a n e m i a

Resistance

M echanism:

a b s c e s s , c e l l u l i t i s , f e v e r , i n f e c t i o n b a c t e r i a l , s e p s i s Respiratory: a d u l t r e s p i r a t o ry d i s t re s s s y n d r o m e , b r o n c h i t i s ,

c o u g h i n g , d y s p n e a , p l e u r is y , p n e u m o n i a , p u l m o n a r y i n f il t ra t i o n , r e s p i r a to r y i n s u f f i 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 t i n g i / r i r a / y : a z o t e m i a , d y s u r i a , h y d r o n e p h r o s i s , k id n e y i n f a r c t i o n , r e n a l f a i l u r e , u r e t e r a l

o b s t r u c t i o n

Vascular (Extracariiac):

b ra i n i n fa r c t io 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 ro p o r t io n o f p a t ie n t s e n r o ll e d i n to th e A T T R A C T tr ia l w h o

r e c e i ve 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 t i m e s t h 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 t o p a t i e n ts t r 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 % ) . F iv e ( 1 . 5 % ) p a t i e n t s tr e a t -

e d w i t h 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 t i o n s i n 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 u p t o 2 0 m g / k g h a v e b e e n a d m i n i s t e r e d w i t h o u t a n y d i r e c t to x i c e f f e c t . I n c a se o f o v e r -

d o s a g e ,i t i s re c o m m e n d e d t h a t th e p a t i e n t b e m o n i t o r e d f o 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 t i o n s o r e f fe c t s

a n d a p p r o p r i a te s y m p t o m a t i c t r e a tm e n t I n s ti tu t e d i m m e d i a t e l y .

S t o r a g e

S t o r e t h 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 f ri g e r a t i o n a t 2 C t o 8 C ( 3 6 F t o 4 6 F ) . D o n o t f r e e z e . D o n o t u s e

b e y o n d t h e e x p i r a t io n d a t e . T h i s p r o d u c t c o n t a i n s n o p r e s e r v a t iv 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 li z e d c o n c e n t r a t e f o r I V i n j e c ti o n i s 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 t h e f o ll o w i n g s t r e n g t h :

N D C 5 7 8 9 4 - 0 3 0 - 0 1 1 0 0 m g i n f li x i m a b i n 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 t e i n A J , M u l l l n G E , S t r 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 f la 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 , F in n J , W o l f e F. D o e s e x p o s u r e t o i m m u n o s u p p r e s s i v e t h 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 t a l it y r is k s i n r h e u m a t o i d a r t h r i t is ? A m a t c h e d c o h o r t s t u d y .

Br JRheum

1 9 9 6 ; 3 5 : 7 3 8 - 4 5 .

C e n t o c o r , I n c ., M a l v e r n , P A 1 9 3 5 5 , U S A

1 - 8 0 0 - 4 5 7 - 6 3 9 9

) C e n t o c o r , In c . 1999 IN99077 7/0 0

L i c e n s e 1 2 4 2

9 N o v e m b e r 1 9 9 9

Centocor

http://www.ccjm.org/http://www.ccjm.org/http://www.ccjm.org/

Documents

Cleveland Clinic Journal of Medicine 2000 880 2