920 Avenue R Bldg. #200 Trimethoprim OS, USP …...Hi-Tech Pharmacal Co., Inc. 16oz....

SULFAMETHOXAZOLEAND TRIMETHOPRIMORAL SUSPENSION, USP200 mg / 40 mg per 5 mL

PHARMACAL PHARMACAL


IMPRINTAREA

RESEALAREA

Hi-Tech Pharmacal Co., Inc.16oz. Sulfamethoxazole and

Trimethoprim OS, USPCherry Flavor

THIS PROOF IS NOT INTENDED FOR COLOR REPRESENTATION. PLEASE REVIEW FOR COPY AND POSITIONING OF GRAPHICS AND TEXT.

APPROVAL SIGNATURE

APPROVED

REVISE AND RE-PROOF

PLATINUM PRESS FAX - (469)733-1510

GRAPHICS PROOFSize:

Rev:

4.125” x 4.125” MC 10/07/11 Copy Position11

Co

py

#4

#4

920 Avenue R Bldg. #200Grand Prairie, TX 75050 (469)733-1506

Healthcare Packaging

BLACK PMS 321GREEN

PMS 485RED

Base Label

Cherry Flavor

Book Placement

Rx only

16 fl oz (473 mL)

Rev. 823:07 7/11

NDC 50383-823-16

50383-823-163 2

4.125"

4.125"

Cherry Flavor

SHAKE WELL BEFORE USING.

16 fl oz (473 mL)

HI-TECH PHARMACAL CO., INC.Amityville, NY 11701

Each teaspoonful (5 mL) contains:Sulfamethoxazole ............................. 200 mgTrimethoprim ..................................... 40 mgAlcohol .............................................. 0.26%

USUAL DOSAGE: See package insert for dosage and full prescribing information.

Dispense in a tight, light-resistant container as defined in the USP. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from light.

1.813" 2.000"

0.313"

Reference ID: 3057440





Front

Cover(Page #1)

Page #20 Page #21 Page #22 Page #23 Page #24 Page #25 Page #26 Page #27 Page #28Page #16 Page #17 Page #18 Page #19


APPROVAL SIGNATURE

APPROVED

REVISE AND RE-PROOF


GRAPHICS PROOFSize:

Rev:

4.125” x 4.125” Copy Position11

Co

py

#4

#4BLACK PMS 321

GREENPMS 485

RED

Info

rmat

ion

for P

atie

nts

Patie

nts

shou

ld b

e co

unse

led

that

ant

ibac

teria

l dru

gs in

clud

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

shou

ld

only

be

used

to tr

eat b

acte

rial i

nfec

tions

. The

y do

not

trea

t vira

l inf

ectio

ns (e

.g.,

the

com

mon

col

d). W

hen

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

is p

resc

ribed

to tr

eat a

bac

teria

l inf

ectio

n, p

atie

nts

shou

ld b

e to

ld th

at

alth

ough

it is

com

mon

to fe

el b

ette

r ear

ly in

the

cour

se o

f the

rapy

, the

med

icat

ion

shou

ld b

e ta

ken

exac

tly a

s di

rect

ed.

Skip

ping

dos

es o

r not

com

plet

ing

the

full

cour

se o

f the

rapy

may

(1) d

ecre

ase

the

effe

ctiv

enes

s of

the

imm

edia

te tr

eatm

ent

and

(2) i

ncre

ase

the

likel

ihoo

d th

at b

acte

ria w

ill d

evel

op re

sist

ance

and

will

not

be

treat

able

by

sulfa

met

hoxa

zole

and

tri

met

hopr

im o

ral s

uspe

nsio

n or

oth

er a

ntib

acte

rial d

rugs

in th

e fu

ture

.Pa

tient

s sh

ould

be

inst

ruct

ed to

mai

ntai

n an

ade

quat

e flu

id in

take

in o

rder

to p

reve

nt c

ryst

allu

ria a

nd s

tone

form

atio

n.Di

arrh

ea is

a c

omm

on p

robl

em c

ause

d by

ant

ibio

tics

whi

ch u

sual

ly e

nds

whe

n th

e an

tibio

tic is

dis

cont

inue

d. S

omet

imes

af

ter s

tarti

ng tr

eatm

ent w

ith a

ntib

iotic

s, p

atie

nts

can

deve

lop

wat

ery

and

bloo

dy s

tool

s (w

ith a

nd w

ithou

t sto

mac

h cr

amps

an

d fe

ver)

eve

n as

late

as

two

or m

ore

mon

ths

afte

r hav

ing

take

n th

e la

st d

ose

of th

e an

tibio

tic. I

f thi

s oc

curs

, pat

ient

s sh

ould

con

tact

thei

r phy

sici

an a

s so

on a

s po

ssib

le.

Labo

rato

ry T

ests

Com

plet

e bl

ood

coun

ts s

houl

d be

don

e fre

quen

tly in

pat

ient

s re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

; if a

sig

nific

ant

redu

ctio

n in

the

coun

t of a

ny fo

rmed

blo

od e

lem

ent i

s no

ted,

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im s

houl

d be

dis

cont

inue

d.

Urin

alys

is w

ith c

aref

ul m

icro

scop

ic e

xam

inat

ion

and

rena

l fun

ctio

n te

sts

shou

ld b

e pe

rform

ed d

urin

g th

erap

y, p

artic

ular

ly

for t

hose

pat

ient

s w

ith im

paire

d re

nal f

unct

ion.

Drug

Inte

ract

ions

In e

lder

ly p

atie

nts

conc

urre

ntly

rece

ivin

g ce

rtain

diu

retic

s, p

rimar

ily th

iazid

es, a

n in

crea

sed

inci

denc

e of

thro

mbo

cyto

peni

a w

ith p

urpu

ra h

as b

een

repo

rted.

It

has

been

repo

rted

that

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay p

rolo

ng th

e pr

othr

ombi

n tim

e in

pat

ient

s w

ho a

re

rece

ivin

g th

e an

ticoa

gula

nt w

arfa

rin. T

his

inte

ract

ion

shou

ld b

e ke

pt in

min

d w

hen

sulfa

met

hoxa

zole

and

trim

etho

prim

is

give

n to

pat

ient

s al

read

y on

ant

icoa

gula

nt th

erap

y, a

nd th

e co

agul

atio

n tim

e sh

ould

be

reas

sess

ed.

Sulfa

met

hoxa

zole

and

trim

etho

prim

may

inhi

bit t

he h

epat

ic m

etab

olis

m o

f phe

nyto

in. S

ulfa

met

hoxa

zole

and

trim

etho

prim

, gi

ven

at a

com

mon

clin

ical

dos

age,

incr

ease

d th

e ph

enyt

oin

half-

life

by 3

9% a

nd d

ecre

ased

the

phen

ytoi

n m

etab

olic

cle

aran

ce

rate

by

27%

. Whe

n ad

min

iste

ring

thes

e dr

ugs

conc

urre

ntly

, one

sho

uld

be a

lert

for p

ossi

ble

exce

ssiv

e ph

enyt

oin

effe

ct.

Sulfo

nam

ides

can

als

o di

spla

ce m

etho

trexa

te fr

om p

lasm

a pr

otei

n bi

ndin

g si

tes

and

can

com

pete

with

the

rena

l tra

nspo

rt of

met

hotre

xate

, thu

s in

crea

sing

free

met

hotre

xate

con

cent

ratio

ns.

Ther

e ha

ve b

een

repo

rts o

f mar

ked

but r

ever

sibl

e ne

phro

toxi

city

with

coa

dmin

istra

tion

of s

ulfa

met

hoxa

zole

and

tri

met

hopr

im a

nd c

yclo

spor

ine

in re

nal t

rans

plan

t rec

ipie

nts.

In

crea

sed

digo

xin

bloo

d le

vels

can

occ

ur w

ith c

onco

mita

nt s

ulfa

met

hoxa

zole

and

trim

etho

prim

ther

apy,

esp

ecia

lly in

el

derly

pat

ient

s. S

erum

dig

oxin

leve

ls s

houl

d be

mon

itore

d.

Incr

ease

d su

lfam

etho

xazo

le b

lood

leve

ls m

ay o

ccur

in p

atie

nts

who

are

als

o re

ceiv

ing

indo

met

haci

n.

Occa

sion

al re

ports

sug

gest

that

pat

ient

s re

ceiv

ing

pyrim

etha

min

e as

mal

aria

pro

phyl

axis

in d

oses

exc

eedi

ng 2

5 m

g w

eekl

y m

ay d

evel

op m

egal

obla

stic

ane

mia

if s

ulfa

met

hoxa

zole

and

trim

etho

prim

is p

resc

ribed

. Th

e ef

ficac

y of

tric

yclic

ant

idep

ress

ants

can

dec

reas

e w

hen

coad

min

iste

red

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im.

Like

oth

er s

ulfo

nam

ide-

cont

aini

ng d

rugs

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im p

oten

tiate

s th

e ef

fect

of o

ral h

ypog

lyce

mic

s.

In th

e lit

erat

ure,

a s

ingl

e ca

se o

f tox

ic d

eliri

um h

as b

een

repo

rted

afte

r con

com

itant

inta

ke o

f su

lfam

etho

xazo

le/tr

imet

hopr

im a

nd a

man

tadi

ne.

In th

e lit

erat

ure,

thre

e ca

ses

of h

yper

kale

mia

in e

lder

ly p

atie

nts

have

bee

n re

porte

d af

ter c

onco

mita

nt in

take

of

sulfa

met

hoxa

zole

/trim

etho

prim

and

an

angi

oten

sin

conv

ertin

g en

zym

e in

hibi

tor.7

,8

Drug

/Lab

orat

ory

Test

Inte

ract

ions

Sulfa

met

hoxa

zole

and

trim

etho

prim

, spe

cific

ally

the

trim

etho

prim

com

pone

nt, c

an in

terfe

re w

ith a

ser

um m

etho

trexa

te

assa

y as

det

erm

ined

by

the

com

petit

ive

bind

ing

prot

ein

tech

niqu

e (C

BPA)

whe

n a

bact

eria

l dih

ydro

fola

te re

duct

ase

is u

sed

as th

e bi

ndin

g pr

otei

n. N

o in

terfe

renc

e oc

curs

, how

ever

, if m

etho

trexa

te is

mea

sure

d by

a ra

dioi

mm

unoa

ssay

(RIA

).Th

e pr

esen

ce o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay a

lso

inte

rfere

with

the

Jaffé

alk

alin

e pi

crat

e re

actio

n as

say

for

crea

tinin

e, re

sulti

ng in

ove

rest

imat

ions

of a

bout

10%

in th

e ra

nge

of n

orm

al v

alue

s.Ca

rcin

ogen

esis

, Mut

agen

esis

, Im

pairm

ent o

f Fer

tility

Carc

inog

enes

is: L

ong-

term

stu

dies

in a

nim

als

to e

valu

ate

carc

inog

enic

pot

entia

l hav

e no

t bee

n co

nduc

ted

with

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im.

Mut

agen

esis

: Bac

teria

l mut

agen

ic s

tudi

es h

ave

not b

een

perfo

rmed

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im in

co

mbi

natio

n. T

rimet

hopr

im w

as d

emon

stra

ted

to b

e no

nmut

agen

ic in

the

Ames

ass

ay. N

o ch

rom

osom

al d

amag

e w

as

obse

rved

in h

uman

leuk

ocyt

es c

ultu

red

in v

itro

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

lone

or i

n co

mbi

natio

n; th

e co

ncen

tratio

ns u

sed

exce

eded

blo

od le

vels

of t

hese

com

poun

ds fo

llow

ing

ther

apy

with

sul

fam

etho

xazo

le a

nd

trim

etho

prim

. Obs

erva

tions

of l

euko

cyte

s ob

tain

ed fr

om p

atie

nts

treat

ed w

ith s

ulfa

met

hoxa

zole

and

trim

etho

prim

reve

aled

no

chr

omos

omal

abn

orm

aliti

es.

Impa

irmen

t of F

ertil

ity: N

o ad

vers

e ef

fect

s on

ferti

lity

or g

ener

al re

prod

uctiv

e pe

rform

ance

wer

e ob

serv

ed in

rats

giv

en

oral

dos

ages

as

high

as

350

mg/

kg/d

ay s

ulfa

met

hoxa

zole

plu

s 70

mg/

kg/d

ay tr

imet

hopr

im.

Preg

nanc

yTe

rato

geni

c Ef

fect

s: P

regn

ancy

Cat

egor

y C.

In ra

ts, o

ral d

oses

of 5

33 m

g/kg

or 2

00 m

g/kg

pro

duce

d te

rato

logi

c ef

fect

s m

anife

sted

mai

nly

as c

left

pala

tes.

Th

e hi

ghes

t dos

e w

hich

did

not

cau

se c

left

pala

tes

in ra

ts w

as 5

12 m

g/kg

sul

fam

etho

xazo

le o

r 192

mg/

kg tr

imet

hopr

im

whe

n ad

min

iste

red

sepa

rate

ly. I

n tw

o st

udie

s in

rats

, no

tera

tolo

gy w

as o

bser

ved

whe

n 51

2 m

g/kg

of s

ulfa

met

hoxa

zole

w

as u

sed

in c

ombi

natio

n w

ith 1

28 m

g/kg

of t

rimet

hopr

im. I

n on

e st

udy,

how

ever

, cle

ft pa

late

s w

ere

obse

rved

in o

ne li

tter

out o

f 9 w

hen

355

mg/

kg o

f sul

fam

etho

xazo

le w

as u

sed

in c

ombi

natio

n w

ith 8

8 m

g/kg

of t

rimet

hopr

im.

In s

ome

rabb

it st

udie

s, a

n ov

eral

l inc

reas

e in

feta

l los

s (d

ead

and

reso

rbed

and

mal

form

ed c

once

ptus

es) w

as a

ssoc

iate

d w

ith d

oses

of t

rimet

hopr

im 6

tim

es th

e hu

man

ther

apeu

tic d

ose.

Whi

le th

ere

are

no la

rge,

wel

l-con

trolle

d st

udie

s on

the

use

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

in p

regn

ant w

omen

, Br

umfit

t and

Pur

sell,

9 in

a re

trosp

ectiv

e st

udy,

repo

rted

the

outc

ome

of 1

86 p

regn

anci

es d

urin

g w

hich

the

mot

her r

ecei

ved

eith

er p

lace

bo o

r sul

fam

etho

xazo

le a

nd tr

imet

hopr

im. T

he in

cide

nce

of c

onge

nita

l abn

orm

aliti

es w

as 4

.5%

(3 o

f 66)

in

thos

e w

ho re

ceiv

ed p

lace

bo a

nd 3

.3%

(4 o

f 120

) in

thos

e re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

. The

re w

ere

no

abno

rmal

ities

in th

e 10

chi

ldre

n w

hose

mot

hers

rece

ived

the

drug

dur

ing

the

first

trim

este

r. In

a s

epar

ate

surv

ey, B

rum

fitt

and

Purs

ell a

lso

foun

d no

con

geni

tal a

bnor

mal

ities

in 3

5 ch

ildre

n w

hose

mot

hers

had

rece

ived

ora

l sul

fam

etho

xazo

le a

nd

trim

etho

prim

at t

he ti

me

of c

once

ptio

n or

sho

rtly

ther

eafte

r.Be

caus

e su

lfam

etho

xazo

le a

nd tr

imet

hopr

im m

ay in

terfe

re w

ith fo

lic a

cid

met

abol

ism

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

shou

ld b

e us

ed d

urin

g pr

egna

ncy

only

if th

e po

tent

ial b

enef

it ju

stifi

es th

e po

tent

ial r

isk

to th

e fe

tus.

Nont

erat

ogen

ic E

ffect

s: S

ee C

ONTR

AIND

ICAT

IONS

sec

tion.

Nurs

ing

Mot

hers

See

CONT

RAIN

DICA

TION

S se

ctio

n.Pe

diat

ric U

seSu

lfam

etho

xazo

le a

nd tr

imet

hopr

im is

not

reco

mm

ende

d fo

r inf

ants

you

nger

than

2 m

onth

s of

age

(see

INDI

CATI

ONS

AND

USAG

E an

d CO

NTRA

INDI

CATI

ONS

sect

ions

).Ge

riatri

c Us

eCl

inic

al s

tudi

es o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im d

id n

ot in

clud

e su

ffici

ent n

umbe

rs o

f sub

ject

s ag

ed 6

5 an

d ov

er to

de

term

ine

whe

ther

they

resp

ond

diffe

rent

ly fr

om y

oung

er s

ubje

cts.

Ther

e m

ay b

e an

incr

ease

d ris

k of

sev

ere

adve

rse

reac

tions

in e

lder

ly p

atie

nts,

par

ticul

arly

whe

n co

mpl

icat

ing

cond

ition

s ex

ist,

e.g.

, im

paire

d ki

dney

and

/or l

iver

func

tion,

pos

sibl

e fo

late

def

icie

ncy,

or c

onco

mita

nt u

se o

f oth

er d

rugs

. Sev

ere

skin

re

actio

ns, g

ener

alize

d bo

ne m

arro

w s

uppr

essi

on (s

ee W

ARNI

NGS

and

ADVE

RSE

REAC

TION

S se

ctio

ns),

a sp

ecifi

c de

crea

se in

pla

tele

ts (w

ith o

r with

out p

urpu

ra),

and

hype

rkal

emia

are

the

mos

t fre

quen

tly re

porte

d se

vere

adv

erse

re

actio

ns in

eld

erly

pat

ient

s. In

thos

e co

ncur

rent

ly re

ceiv

ing

certa

in d

iure

tics,

prim

arily

thia

zides

, an

incr

ease

d in

cide

nce

of

thro

mbo

cyto

peni

a w

ith p

urpu

ra h

as b

een

repo

rted.

Incr

ease

d di

goxi

n bl

ood

leve

ls c

an o

ccur

with

con

com

itant

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im th

erap

y, e

spec

ially

in e

lder

ly p

atie

nts.

Ser

um d

igox

in le

vels

sho

uld

be m

onito

red.

He

mat

olog

ical

cha

nges

indi

cativ

e of

folic

aci

d de

ficie

ncy

may

occ

ur in

eld

erly

pat

ient

s. T

hese

effe

cts

are

reve

rsib

le b

y fo

linic

aci

d th

erap

y. A

ppro

pria

te d

osag

e ad

just

men

ts s

houl

d be

mad

e fo

r pat

ient

s w

ith im

paire

d ki

dney

func

tion

and

dura

tion

of u

se s

houl

d be

as

shor

t as

poss

ible

to m

inim

ize ri

sks

of u

ndes

ired

reac

tions

(see

DOS

AGE

AND

ADM

INIS

TRAT

ION

sect

ion)

. The

trim

etho

prim

com

pone

nt o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay c

ause

hyp

erka

lem

ia

whe

n ad

min

iste

red

to p

atie

nts

with

und

erly

ing

diso

rder

s of

pot

assi

um m

etab

olis

m, w

ith re

nal i

nsuf

ficie

ncy

or w

hen

give

n co

ncom

itant

ly w

ith d

rugs

kno

wn

to in

duce

hyp

erka

lem

ia, s

uch

as a

ngio

tens

in c

onve

rting

enz

yme

inhi

bito

rs. C

lose

m

onito

ring

of s

erum

pot

assi

um is

war

rant

ed in

thes

e pa

tient

s. D

isco

ntin

uatio

n of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

treat

men

t is

reco

mm

ende

d to

hel

p lo

wer

pot

assi

um s

erum

leve

ls.

Phar

mac

okin

etic

s pa

ram

eter

s fo

r sul

fam

etho

xazo

le w

ere

sim

ilar f

or g

eria

tric

subj

ects

and

you

nger

adu

lt su

bjec

ts. T

he

mea

n m

axim

um s

erum

trim

etho

prim

con

cent

ratio

n w

as h

ighe

r and

mea

n re

nal c

lear

ance

of t

rimet

hopr

im w

as lo

wer

in

geria

tric

subj

ects

com

pare

d w

ith y

oung

er s

ubje

cts

(see

CLI

NICA

L PH

ARM

ACOL

OGY:

Ger

iatri

c Ph

arm

acok

inet

ics)

.AD

VERS

E RE

ACTI

ONS

The

mos

t com

mon

adv

erse

effe

cts

are

gast

roin

test

inal

dis

turb

ance

s (n

ause

a, v

omiti

ng, a

nore

xia)

and

alle

rgic

ski

n re

actio

ns (s

uch

as ra

sh a

nd u

rtica

ria).

FATA

LITI

ES A

SSOC

IATE

D W

ITH

THE

ADM

INIS

TRAT

ION

OF S

ULFO

NAM

IDES

, AL

THOU

GH R

ARE,

HAV

E OC

CURR

ED D

UE T

O SE

VERE

REA

CTIO

NS, I

NCLU

DING

STE

VENS

-JOH

NSON

SYN

DROM

E,

TOXI

C EP

IDER

MAL

NEC

ROLY

SIS,

FUL

MIN

ANT

HEPA

TIC

NECR

OSIS

, AGR

ANUL

OCYT

OSIS

, APL

ASTI

C AN

EMIA

AND

OT

HER

BLOO

D DY

SCRA

SIAS

(SEE

WAR

NING

S SE

CTIO

N).

Hem

atol

ogic

: Agr

anul

ocyt

osis

, apl

astic

ane

mia

, thr

ombo

cyto

peni

a, le

ukop

enia

, neu

trope

nia,

hem

olyt

ic a

nem

ia,

meg

alob

last

ic a

nem

ia, h

ypop

roth

rom

bine

mia

, met

hem

oglo

bine

mia

, eos

inop

hilia

.Al

lerg

ic R

eact

ions

: Ste

vens

-Joh

nson

syn

drom

e, to

xic

epid

erm

al n

ecro

lysi

s, a

naph

ylax

is, a

llerg

ic m

yoca

rditi

s, e

ryth

ema

mul

tifor

me,

exf

olia

tive

derm

atiti

s, a

ngio

edem

a, d

rug

feve

r, ch

ills,

Hen

och-

Schö

enle

in p

urpu

ra, s

erum

sic

knes

s-lik

e sy

ndro

me,

gen

eral

ized

alle

rgic

reac

tions

, gen

eral

ized

skin

eru

ptio

ns, p

hoto

sens

itivi

ty, c

onju

nctiv

al a

nd s

cler

al in

ject

ion,

pr

uritu

s, u

rtica

ria a

nd ra

sh. I

n ad

ditio

n, p

eria

rterit

is n

odos

a an

d sy

stem

ic lu

pus

eryt

hem

atos

us h

ave

been

repo

rted.

Gast

roin

test

inal

: Hep

atiti

s, (i

nclu

ding

cho

lest

atic

jaun

dice

and

hep

atic

nec

rosi

s), e

leva

tion

of s

erum

tran

sam

inas

e an

d bi

lirub

in,

pseu

dom

embr

anou

s en

tero

colit

is, p

ancr

eatit

is, s

tom

atiti

s, g

loss

itis,

nau

sea,

em

esis

, abd

omin

al p

ain,

dia

rrhe

a, a

nore

xia.

Geni

tour

inar

y: R

enal

failu

re, i

nter

stiti

al n

ephr

itis,

BUN

and

ser

um c

reat

inin

e el

evat

ion,

toxi

c ne

phro

sis

with

olig

uria

and

an

uria

, cry

stal

luria

and

nep

hrot

oxic

ity in

ass

ocia

tion

with

cyc

losp

orin

e.M

etab

olic

and

Nut

ritio

nal:

Hype

rkal

emia

(see

PRE

CAUT

IONS

: Use

in th

e Tr

eatm

ent o

f and

Pro

phyl

axis

for

Pneu

moc

ystis

Car

inii

Pneu

mon

ia in

Pat

ient

s w

ith A

cqui

red

Imm

unod

efic

ienc

y Sy

ndro

me

(AID

S).

Neur

olog

ic: A

sept

ic m

enin

gitis

, con

vuls

ions

, per

iphe

ral n

eurit

is, a

taxi

a, v

ertig

o, ti

nnitu

s, h

eada

che.

Psyc

hiat

ric: H

allu

cina

tions

, dep

ress

ion,

apa

thy,

ner

vous

ness

.En

docr

ine:

The

sul

fona

mid

es b

ear c

erta

in c

hem

ical

sim

ilarit

ies

to s

ome

goitr

ogen

s, d

iure

tics

(ace

tazo

lam

ide

and

the

thia

zides

) and

ora

l hyp

ogly

cem

ic a

gent

s. C

ross

-sen

sitiv

ity m

ay e

xist

with

thes

e ag

ents

. Diu

resi

s an

d hy

pogl

ycem

ia h

ave

occu

rred

rare

ly in

pat

ient

s re

ceiv

ing

sulfo

nam

ides

.M

uscu

losk

elet

al: A

rthra

lgia

and

mya

lgia

. Iso

late

d ca

ses

of rh

abdo

myo

lysi

s ha

ve b

een

repo

rted

with

sul

fam

etho

xazo

le a

nd

trim

etho

prim

, mai

nly

in A

IDS

patie

nts.

Resp

irato

ry: C

ough

, sho

rtnes

s of

bre

ath

and

pulm

onar

y in

filtra

tes

(see

WAR

NING

S).

Mis

cella

neou

s: W

eakn

ess,

fatig

ue, i

nsom

nia.

Post

mar

ketin

g Ex

perie

nce

The

follo

win

g ad

vers

e re

actio

ns h

ave

been

iden

tifie

d du

ring

post

-app

rova

l use

of t

rimet

hopr

im-s

ulfa

met

hoxa

zole

. Bec

ause

th

ese

reac

tions

wer

e re

porte

d vo

lunt

arily

from

a p

opul

atio

n of

unc

erta

in s

ize, i

t is

not p

ossi

ble

to re

liabl

y es

timat

e th

eir

frequ

ency

or e

stab

lish

a ca

usal

rela

tions

hip

to d

rug

expo

sure

:Σ

Thr

ombo

tic th

rom

bocy

tope

nia

purp

ura

Σ Id

iopa

thic

thro

mbo

cyto

peni

c pu

rpur

aOV

ERDO

SAGE

Acut

e: T

he a

mou

nt o

f a s

ingl

e do

se o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im th

at is

eith

er a

ssoc

iate

d w

ith s

ympt

oms

of

over

dosa

ge o

r is

likel

y to

be

life-

thre

aten

ing

has

not b

een

repo

rted.

Sig

ns a

nd s

ympt

oms

of o

verd

osag

e re

porte

d w

ith

sulfo

nam

ides

incl

ude

anor

exia

, col

ic, n

ause

a, v

omiti

ng, d

izzin

ess,

hea

dach

e, d

row

sine

ss a

nd u

ncon

scio

usne

ss. P

yrex

ia,

hem

atur

ia a

nd c

ryst

allu

ria m

ay b

e no

ted.

Blo

od d

yscr

asia

s an

d ja

undi

ce a

re p

oten

tial l

ate

man

ifest

atio

ns o

f ove

rdos

age.

Si

gns

of a

cute

ove

rdos

age

with

trim

etho

prim

incl

ude

naus

ea, v

omiti

ng, d

izzin

ess,

hea

dach

e, m

enta

l dep

ress

ion,

con

fusi

on

and

bone

mar

row

dep

ress

ion.

Ge

nera

l prin

cipl

es o

f tre

atm

ent i

nclu

de th

e in

stitu

tion

of g

astri

c la

vage

or e

mes

is, f

orci

ng o

ral f

luid

s, a

nd th

e ad

min

istra

tion

of in

trave

nous

flui

ds if

urin

e ou

tput

is lo

w a

nd re

nal f

unct

ion

is n

orm

al. A

cidi

ficat

ion

of th

e ur

ine

will

incr

ease

rena

l el

imin

atio

n of

trim

etho

prim

. The

pat

ient

sho

uld

be m

onito

red

with

blo

od c

ount

s an

d ap

prop

riate

blo

od c

hem

istri

es,

incl

udin

g el

ectro

lyte

s. If

a s

igni

fican

t blo

od d

yscr

asia

or j

aund

ice

occu

rs, s

peci

fic th

erap

y sh

ould

be

inst

itute

d fo

r the

se

com

plic

atio

ns. P

erito

neal

dia

lysi

s is

not

effe

ctiv

e an

d he

mod

ialy

sis

is o

nly

mod

erat

ely

effe

ctiv

e in

elim

inat

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

.Ch

roni

c: U

se o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

t hig

h do

ses

and/

or fo

r ext

ende

d pe

riods

of t

ime

may

cau

se b

one

mar

row

dep

ress

ion

man

ifest

ed a

s th

rom

bocy

tope

nia,

leuk

open

ia a

nd/o

r meg

alob

last

ic a

nem

ia. I

f sig

ns o

f bon

e m

arro

w

depr

essi

on o

ccur

, the

pat

ient

sho

uld

be g

iven

leuc

ovor

in 5

to 1

5 m

g da

ily u

ntil

norm

al h

emat

opoi

esis

is re

stor

ed.

DOSA

GE A

ND A

DMIN

ISTR

ATIO

NNo

t rec

omm

ende

d fo

r use

in p

edia

tric

patie

nts

less

than

2 m

onth

s of

age

.Ur

inar

y Tr

act I

nfec

tions

and

Shi

gello

sis

in A

dults

and

Ped

iatri

c Pa

tient

s, a

nd A

cute

Otit

is M

edia

in C

hild

ren:

Adul

ts: T

he u

sual

adu

lt do

sage

in th

e tre

atm

ent o

f urin

ary

tract

infe

ctio

ns is

four

teas

poon

fuls

(20

mL)

sul

fam

etho

xazo

le

and

trim

etho

prim

ora

l sus

pens

ion

ever

y 12

hou

rs fo

r 10

to 1

4 da

ys. A

n id

entic

al d

aily

dos

age

is u

sed

for 5

day

s in

the

treat

men

t of s

hige

llosi

s.Ch

ildre

n: T

he re

com

men

ded

dose

for c

hild

ren

with

urin

ary

tract

infe

ctio

ns o

r acu

te o

titis

med

ia is

40

mg/

kg

sulfa

met

hoxa

zole

and

8 m

g/kg

trim

etho

prim

per

24

hour

s, g

iven

in tw

o di

vide

d do

ses

ever

y 12

hou

rs fo

r 10

days

. An

iden

tical

dai

ly d

osag

e is

use

d fo

r 5 d

ays

in th

e tre

atm

ent o

f shi

gello

sis.

The

follo

win

g ta

ble

is a

gui

delin

e fo

r the

atta

inm

ent

of th

is d

osag

e:

Acut

e Ex

acer

batio

ns o

f Chr

onic

Bro

nchi

tis in

Adu

lts:

The

usua

l adu

lt do

sage

in th

e tre

atm

ent o

f acu

te e

xace

rbat

ions

of c

hron

ic b

ronc

hitis

is fo

ur te

aspo

onfu

ls (2

0 m

L)

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

ever

y 12

hou

rs fo

r 14

days

.Pn

eum

ocys

tis C

arin

ii Pn

eum

onia

:Tr

eatm

ent:

Adul

ts a

nd C

hild

ren:

The

reco

mm

ende

d do

sage

for t

reat

men

t of p

atie

nts

with

doc

umen

ted

Pneu

moc

ystis

ca

rinii

pneu

mon

ia is

75

to 1

00 m

g/kg

sul

fam

etho

xazo

le a

nd 1

5 to

20

mg/

kg tr

imet

hopr

im p

er 2

4 ho

urs

give

n in

equ

ally

di

vide

d do

ses

ever

y 6

hour

s fo

r 14

to 2

1 da

ys.1

0 T

he fo

llow

ing

tabl

e is

a g

uide

line

for t

he u

pper

lim

it of

this

dos

age:

For t

he lo

wer

lim

it do

se (7

5 m

g/kg

sul

fam

etho

xazo

le a

nd 1

5 m

g/kg

trim

etho

prim

per

24

hour

s) a

dmin

iste

r 75%

of t

he

dose

in th

e ab

ove

tabl

e.Pr

ophy

laxi

s:Ad

ults

: The

reco

mm

ende

d do

sage

for p

roph

ylax

is in

adu

lts is

four

teas

poon

fuls

(20

mL)

of t

he o

ral s

uspe

nsio

n da

ily.1

1Ch

ildre

n: F

or c

hild

ren,

the

reco

mm

ende

d do

se is

750

mg/

m2 /

day

sulfa

met

hoxa

zole

with

150

mg/

m2 /

day

trim

etho

prim

gi

ven

oral

ly in

equ

ally

div

ided

dos

es tw

ice

a da

y, o

n 3

cons

ecut

ive

days

per

wee

k. T

he to

tal d

aily

dos

e sh

ould

not

exc

eed

1600

mg

sulfa

met

hoxa

zole

and

320

mg

trim

etho

prim

.12

The

follo

win

g ta

ble

is a

gui

delin

e fo

r the

atta

inm

ent o

f thi

s do

sage

in c

hild

ren:

Trav

eler

's D

iarr

hea

in A

dults

: Fo

r the

trea

tmen

t of t

rave

ler's

dia

rrhe

a, th

e us

ual a

dult

dosa

ge is

four

teas

poon

fuls

(20

mL)

of s

ulfa

met

hoxa

zole

and

tri

met

hopr

im o

ral s

uspe

nsio

n ev

ery

12 h

ours

for 5

day

s.

HOW

SUP

PLIE

DSu

lfam

etho

xazo

le a

nd T

rimet

hopr

im O

ral S

uspe

nsio

n, U

SP is

sup

plie

d in

a p

urpl

e gr

ape-

flavo

red

susp

ensi

on a

nd in

a p

ink

cher

ry-fl

avor

ed s

uspe

nsio

n co

ntai

ning

200

mg

sulfa

met

hoxa

zole

and

40

mg

trim

etho

prim

per

5 m

L (te

aspo

onfu

l) bo

th

pack

aged

in 1

pin

t (47

3 m

L) b

ottle

s.St

ore

at 2

0°-2

5°C

(68°

-77°

F) [s

ee U

SP C

ontro

lled

Room

Tem

pera

ture

]. Pr

otec

t fro

m li

ght.

SHAK

E W

ELL

BEFO

RE U

SING

.Di

spen

se in

a ti

ght,

light

-res

ista

nt c

onta

iner

as

defin

ed in

the

USP,

with

a c

hild

-res

ista

nt c

losu

re (a

s re

quire

d).

To re

port

SUSP

ECTE

D AD

VERS

E RE

ACTI

ONS,

con

tact

Hi-T

ech

Phar

mac

al, C

o., I

nc. a

t 1-8

00-2

62-9

010

or F

DA a

t 1-

800-

FDA-

1088

or w

ww

.fda.

gov/

med

wat

ch.

Rx o

nly

REFE

RENC

ES1.

Kr

emer

s P,

Duv

ivie

r J, H

eusg

hem

C. P

harm

acok

inet

ic S

tudi

es o

f Co-

Trim

oxaz

ole

in M

an a

fter S

ingl

e an

d Re

peat

edDo

ses.

J C

lin P

harm

acol

. Feb

-Mar

197

4; 1

4:11

2–11

7.

2.

Kapl

an S

A, e

t al.

Phar

mac

okin

etic

Pro

file

of T

rimet

hopr

im-S

ulfa

met

hoxa

zole

in M

an. J

Infe

ct D

is. N

ov 1

973;

128

(Sup

pl):

S547

–S55

5.

3.

Varo

quau

x O,

et a

l. Ph

arm

acok

inet

ics

of th

e tri

met

hopr

im-s

ulfa

met

hoxa

zole

com

bina

tion

in th

e el

derly

.Br

J C

lin P

harm

acol

. 198

5;20

:575

–581

. 4.

Ru

doy

RC, N

elso

n JD

, Hal

talin

KC.

Ant

imic

robi

al A

gent

s Ch

emot

her.

May

197

4;5:

439–

443.

5.

Na

tiona

l Com

mitt

ee fo

r Clin

ical

Lab

orat

ory

Stan

dard

s. M

etho

ds fo

r Dilu

tion

Antim

icro

bial

Sus

cept

ibili

ty T

ests

for

Bact

eria

that

Gro

w A

erob

ical

ly; A

ppro

ved

Stan

dard

– F

ourth

Edi

tion.

NCC

LS D

ocum

ent M

7–A4

, Vol

.17,

No.

2, N

CCLS

, W

ayne

, PA,

Jan

uary

, 199

7.

6.

Hard

y DW

, et a

l. A

cont

rolle

d tri

al o

f trim

etho

prim

-sul

fam

etho

xazo

le o

r aer

osol

ized

pent

amid

ine

for s

econ

dary

prop

hyla

xis

of P

neum

ocys

tis c

arin

ii pn

eum

onia

in p

atie

nts

with

the

acqu

ired

imm

unod

efic

ienc

y sy

ndro

me.

N En

gl J

Med

. 199

2; 3

27: 1

842–

1848

. 7.

M

arin

ella

Mar

k A.

199

9. T

rimet

hopr

im-in

duce

d hy

perk

alem

ia: A

n an

alys

is o

f rep

orte

d ca

ses.

Ger

onto

l. 45

:209

–212

. 8.

M

arga

sser

y, S

. and

B. B

asta

ni. 2

002.

Life

thre

aten

ing

hype

rkal

emia

and

aci

dosi

s se

cond

ary

totri

met

hopr

im-s

ulfa

met

hoxa

zole

trea

tmen

t. J.

Nep

hrol

. 14:

410–

414.

9.

Br

umfit

t W, P

urse

ll R.

Trim

etho

prim

/Sul

fam

etho

xazo

le in

the

Trea

tmen

t of B

acte

riuria

in W

omen

. J In

fect

Dis

.No

v 19

73; 1

28 (S

uppl

):S65

7–S6

63.

10. M

asur

H. P

reve

ntio

n an

d tre

atm

ent o

f Pne

umoc

ystis

pne

umon

ia. N

Eng

l J M

ed. 1

992;

327

: 185

3–18

80.

11. R

ecom

men

datio

ns fo

r pro

phyl

axis

aga

inst

Pne

umoc

ystis

car

inii

pneu

mon

ia fo

r adu

lts a

nd a

dole

scen

ts in

fect

ed w

ithhu

man

imm

unod

efic

ienc

y vi

rus.

MM

WR.

199

2; 4

1(RR

-4):1

–11.

12

. CDC

Gui

delin

es fo

r pro

phyl

axis

aga

inst

Pne

umoc

ystis

car

inii

pneu

mon

ia fo

r chi

ldre

n in

fect

ed w

ith h

uman

imm

unod

efic

ienc

y vi

rus.

MM

WR.

199

1; 4

0(RR

-2):1

–13.

M

anuf

actu

red

by:

Hi-T

ech

Phar

mac

al C

o., I

nc.

Rev.

823

:07

7/11

Amity

ville

, New

Yor

k 11

701

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APPROVAL SIGNATURE

APPROVED

REVISE AND RE-PROOF


GRAPHICS PROOFSize:

Rev:


Co

py

#4

#4BLACK

Page #8 Page #9 Page #10Page #3 Page #4 Page #5 Page #6 Page #7Page #2(Back of Cover)

Page #11 Page #12 Page #13 Page #14 Page #15

CH

3

HN 2

SO

NH

2

NO

N

N

NH

2

CH

2N

H2

CH

O3

OC

H3

OC

H3

SULF

AMET

HOXA

ZOLE

AND

TRI

MET

HOPR

IMOR

AL S

USPE

NSIO

N, U

SPTo

redu

ce th

e de

velo

pmen

t of d

rug-

resi

stan

t bac

teria

and

mai

ntai

n th

e ef

fect

iven

ess

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

or

al s

uspe

nsio

n an

d ot

her a

ntib

acte

rial d

rugs

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im o

ral s

uspe

nsio

n sh

ould

be

used

onl

y to

tre

at o

r pre

vent

infe

ctio

ns th

at a

re p

rove

n or

stro

ngly

sus

pect

ed to

be

caus

ed b

y ba

cter

ia.

DESC

RIPT

ION

Sulfa

met

hoxa

zole

and

trim

etho

prim

is a

syn

thet

ic a

ntib

acte

rial c

ombi

natio

n pr

oduc

t con

tain

ing

200

mg

sulfa

met

hoxa

zole

an

d 40

mg

trim

etho

prim

per

5 m

L fo

r ora

l adm

inis

tratio

n.

Sulfa

met

hoxa

zole

is N

1 -(5

-met

hyl-3

-isox

azol

yl)s

ulfa

nila

mid

e; th

e m

olec

ular

form

ula

is C

10H 1

1N3O

3S. I

t is

an a

lmos

t whi

te,

odor

less

, tas

tele

ss c

ompo

und

with

a m

olec

ular

wei

ght o

f 253

.28

and

the

follo

win

g st

ruct

ural

form

ula:

Trim

etho

prim

is 2

,4-d

iam

ino-

5-(3

,4,5

-trim

etho

xybe

nzyl

)pyr

imid

ine;

the

mol

ecul

ar fo

rmul

a is

C14

H 18N

4O3.

It is

a w

hite

to

light

yel

low

, odo

rless

, bitt

er c

ompo

und

with

a m

olec

ular

wei

ght o

f 290

.3 a

nd th

e fo

llow

ing

stru

ctur

al fo

rmul

a:

Inac

tive

ingr

edie

nts:

alc

ohol

0.2

6%, m

ethy

lpar

aben

0.1

% a

nd s

odiu

m b

enzo

ate

0.1%

(add

ed a

s pr

eser

vativ

es),

carb

oxym

ethy

lcel

lulo

se s

odiu

m, c

itric

aci

d (a

nhyd

rous

), gl

ycer

in, m

icro

crys

talli

ne c

ellu

lose

, pol

ysor

bate

80,

pur

ified

wat

er,

sacc

harin

sod

ium

, and

sor

bito

l. Th

e lig

ht p

urpl

e, g

rape

flav

ored

sus

pens

ion

cont

ains

the

follo

win

g ad

ditio

nal i

nact

ive

ingr

edie

nts:

FD&

C Re

d No

. 40,

FD&

C Bl

ue N

o. 1

and

nat

ural

and

arti

ficia

l gra

pe fl

avor

. The

pin

k, c

herr

y fla

vore

d su

spen

sion

co

ntai

ns th

e fo

llow

ing

addi

tiona

l ina

ctiv

e in

gred

ient

s: F

D&C

Red

No. 4

0, F

D&C

Yello

w N

o. 6

and

arti

ficia

l che

rry

flavo

r.CL

INIC

AL P

HARM

ACOL

OGY

Sulfa

met

hoxa

zole

and

trim

etho

prim

is ra

pidl

y ab

sorb

ed fo

llow

ing

oral

adm

inis

tratio

n. B

oth

sulfa

met

hoxa

zole

and

tri

met

hopr

im e

xist

in th

e bl

ood

as u

nbou

nd, p

rote

in-b

ound

and

met

abol

ized

form

s; s

ulfa

met

hoxa

zole

als

o ex

ists

as

the

conj

ugat

ed fo

rm. T

he m

etab

olis

m o

f sul

fam

etho

xazo

le o

ccur

s pr

edom

inat

ely

by N

4-ac

etyl

atio

n, a

lthou

gh th

e gl

ucur

onid

e co

njug

ate

has

been

iden

tifie

d. T

he p

rinci

pal m

etab

olite

s of

trim

etho

prim

are

the

1- a

nd 3

-oxi

des

and

the

3’- a

nd 4

’-hyd

roxy

de

rivat

ives

. The

free

form

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re c

onsi

dere

d to

be

the

ther

apeu

tical

ly a

ctiv

e fo

rms.

Ap

prox

imat

ely

70%

of s

ulfa

met

hoxa

zole

and

44%

of t

rimet

hopr

im a

re b

ound

to p

lasm

a pr

otei

ns. T

he p

rese

nce

of 1

0 m

g pe

rcen

t sul

fam

etho

xazo

le in

pla

sma

decr

ease

s th

e pr

otei

n bi

ndin

g of

trim

etho

prim

by

an in

sign

ifica

nt d

egre

e; tr

imet

hopr

im

does

not

influ

ence

the

prot

ein

bind

ing

of s

ulfa

met

hoxa

zole

.Pe

ak b

lood

leve

ls fo

r the

indi

vidu

al c

ompo

nent

s oc

cur 1

to 4

hou

rs a

fter o

ral a

dmin

istra

tion.

The

mea

n se

rum

hal

f-liv

es o

f su

lfam

etho

xazo

le a

nd tr

imet

hopr

im a

re 1

0 an

d 8

to 1

0 ho

urs,

resp

ectiv

ely.

How

ever

, pat

ient

s w

ith s

ever

ely

impa

ired

rena

l fu

nctio

n ex

hibi

t an

incr

ease

in th

e ha

lf-liv

es o

f bot

h co

mpo

nent

s, re

quiri

ng d

osag

e re

gim

en a

djus

tmen

t (se

e DO

SAGE

AND

AD

MIN

ISTR

ATIO

N se

ctio

n). D

etec

tabl

e am

ount

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re p

rese

nt in

the

bloo

d 24

hou

rs

afte

r dru

g ad

min

istra

tion.

Dur

ing

adm

inis

tratio

n of

800

mg

sulfa

met

hoxa

zole

and

160

mg

trim

etho

prim

b.i.

d., t

he m

ean

stea

dy-s

tate

pla

sma

conc

entra

tion

of tr

imet

hopr

im w

as 1

.72

μg/

mL.

The

ste

ady-

stat

e m

ean

plas

ma

leve

ls o

f fre

e an

d to

tal

sulfa

met

hoxa

zole

wer

e 57

.4 μ

g/m

L an

d 68

.0 μ

g/m

L, re

spec

tivel

y. T

hese

ste

ady-

stat

e le

vels

wer

e ac

hiev

ed a

fter t

hree

day

s of

dru

g ad

min

istra

tion.

1 Ex

cret

ion

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

is p

rimar

ily b

y th

e ki

dney

s th

roug

h bo

th

glom

erul

ar fi

ltrat

ion

and

tubu

lar s

ecre

tion.

Urin

e co

ncen

tratio

ns o

f bot

h su

lfam

etho

xazo

le a

nd tr

imet

hopr

im a

re

cons

ider

ably

hig

her t

han

are

the

conc

entra

tions

in th

e bl

ood.

The

ave

rage

per

cent

age

of th

e do

se re

cove

red

in u

rine

from

0

to 7

2 ho

urs

afte

r a s

ingl

e or

al d

ose

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

is 8

4.5%

for t

otal

sul

fona

mid

e an

d 66

.8%

for

free

trim

etho

prim

. Thi

rty p

erce

nt o

f the

tota

l sul

fona

mid

e is

exc

rete

d as

free

sul

fam

etho

xazo

le, w

ith th

e re

mai

ning

as

N 4-a

cety

late

d m

etab

olite

.2 W

hen

adm

inis

tere

d to

geth

er a

s su

lfam

etho

xazo

le a

nd tr

imet

hopr

im, n

eith

er s

ulfa

met

hoxa

zole

no

r trim

etho

prim

affe

cts

the

urin

ary

excr

etio

n pa

ttern

of t

he o

ther

.Bo

th s

ulfa

met

hoxa

zole

and

trim

etho

prim

dis

tribu

te to

spu

tum

, vag

inal

flui

d an

d m

iddl

e ea

r flu

id; t

rimet

hopr

im a

lso

dist

ribut

es to

bro

nchi

al s

ecre

tions

, and

bot

h pa

ss th

e pl

acen

tal b

arrie

r and

are

exc

rete

d in

hum

an m

ilk.

Geria

tric

Phar

mac

okin

etic

sTh

e ph

arm

acok

inet

ics

of s

ulfa

met

hoxa

zole

800

mg

and

trim

etho

prim

160

mg

wer

e st

udie

d in

6 g

eria

tric

subj

ects

(mea

n ag

e: 7

8.6

year

s) a

nd 6

you

ng h

ealth

y su

bjec

ts (m

ean

age:

29.

3 ye

ars)

usi

ng a

non

-U.S

. app

rove

d fo

rmul

atio

n.

Phar

mac

okin

etic

val

ues

for s

ulfa

met

hoxa

zole

in g

eria

tric

subj

ects

wer

e si

mila

r to

thos

e ob

serv

ed in

you

ng a

dult

subj

ects

. Th

e m

ean

rena

l cle

aran

ce o

f trim

etho

prim

was

sig

nific

antly

low

er in

ger

iatri

c su

bjec

ts c

ompa

red

with

you

ng a

dult

subj

ects

(1

9 m

L/h/

kg v

s. 5

5 m

L/h/

kg).

How

ever

, afte

r nor

mal

izing

by

body

wei

ght,

the

appa

rent

tota

l bod

y cl

eara

nce

of

trim

etho

prim

was

on

aver

age

19%

low

er in

ger

iatri

c su

bjec

ts c

ompa

red

with

you

ng a

dult

subj

ects

.3M

icro

biol

ogy

Sulfa

met

hoxa

zole

inhi

bits

bac

teria

l syn

thes

is o

f dih

ydro

folic

aci

d by

com

petin

g w

ith p

ara-

amin

oben

zoic

aci

d (P

ABA)

. Tr

imet

hopr

im b

lock

s th

e pr

oduc

tion

of te

trahy

drof

olic

aci

d fro

m d

ihyd

rofo

lic a

cid

by b

indi

ng to

and

reve

rsib

ly in

hibi

ting

the

requ

ired

enzy

me,

dih

ydro

fola

te re

duct

ase.

Thu

s, s

ulfa

met

hoxa

zole

and

trim

etho

prim

blo

cks

two

cons

ecut

ive

step

s in

th

e bi

osyn

thes

is o

f nuc

leic

aci

ds a

nd p

rote

ins

esse

ntia

l to

man

y ba

cter

ia.

In v

itro

stud

ies

have

sho

wn

that

bac

teria

l res

ista

nce

deve

lops

mor

e sl

owly

with

bot

h su

lfam

etho

xazo

le a

nd tr

imet

hopr

im in

co

mbi

natio

n th

an w

ith e

ither

sul

fam

etho

xazo

le o

r trim

etho

prim

alo

ne.

Sulfa

met

hoxa

zole

and

trim

etho

prim

hav

e be

en s

how

n to

be

activ

e ag

ains

t mos

t stra

ins

of th

e fo

llow

ing

mic

roor

gani

sms,

bo

th in

vitr

o an

d in

clin

ical

infe

ctio

ns a

s de

scrib

ed in

the

INDI

CATI

ONS

AND

USAG

E se

ctio

n.Ae

robi

c gr

am-p

ositi

ve m

icro

orga

nism

s:

Stre

ptoc

occu

s pn

eum

onia

e Ae

robi

c gr

am-n

egat

ive

mic

roor

gani

sms:

Es

cher

ichi

a co

li (in

clud

ing

susc

eptib

le e

nter

otox

igen

ic s

train

s im

plic

ated

in tr

avel

er's

dia

rrhe

a)Kl

ebsi

ella

spe

cies

Ente

roba

cter

spe

cies

Haem

ophi

lus

influ

enza

eM

orga

nella

mor

gani

iPr

oteu

s m

irabi

lisPr

oteu

s vu

lgar

isSh

igel

la fl

exne

riSh

igel

la s

onne

iOt

her O

rgan

ism

s:

Pneu

moc

ystis

car

inii

Susc

eptib

ility

Tes

ting

Met

hods

: Di

lutio

n Te

chni

ques

: Qu

antit

ativ

e m

etho

ds a

re u

sed

to d

eter

min

e an

timic

robi

al m

inim

um in

hibi

tory

con

cent

ratio

ns (M

ICs)

. The

se M

ICs

prov

ide

estim

ates

of t

he s

usce

ptib

ility

of b

acte

ria to

ant

imic

robi

al c

ompo

unds

. The

MIC

s sh

ould

be

dete

rmin

ed u

sing

a

stan

dard

ized

proc

edur

e. S

tand

ardi

zed

proc

edur

es a

re b

ased

on

a di

lutio

n m

etho

d4 (b

roth

or a

gar)

or e

quiv

alen

t with

st

anda

rdize

d in

ocul

um c

once

ntra

tions

and

sta

ndar

dize

d co

ncen

tratio

ns o

f sul

fam

etho

xazo

le/tr

imet

hopr

im p

owde

r. Th

e M

IC v

alue

s sh

ould

be

inte

rpre

ted

acco

rdin

g to

the

follo

win

g cr

iteria

: Fo

r tes

ting

Ente

roba

cter

iace

ae:

MIC

(μg/

mL)

In

terp

reta

tion

≤ 2/

38

Susc

eptib

le (S

)≥

4/76

Re

sist

ant (

R)W

hen

test

ing

eith

er H

aem

ophi

lus

influ

enza

ea o

r Stre

ptoc

occu

s pn

eum

onia

eb:

MIC

(μg/

mL)

In

terp

reta

tionb

≤ 0.

5/9.

5 Su

scep

tible

(S)

1/19

– 2

/38

Inte

rmed

iate

(I)

≥ 4/

76

Resi

stan

t (R)

a.Th

ese

inte

rpre

tativ

e st

anda

rds

are

appl

icab

le o

nly

to b

roth

mic

rodi

lutio

n su

scep

tibili

ty te

sts

with

Hae

mop

hilu

s in

fluen

zae

usin

g Ha

emop

hilu

s Te

st M

ediu

m (H

TM).4

b.

Thes

e in

terp

reta

tive

stan

dard

s ar

e ap

plic

able

onl

y to

bro

th m

icro

dilu

tion

susc

eptib

ility

test

s us

ing

catio

n-ad

just

edM

uelle

r-Hi

nton

bro

th w

ith 2

% to

5%

lyse

d ho

rse

bloo

d.4

A re

port

of "S

usce

ptib

le" i

ndic

ates

that

the

path

ogen

is li

kely

to b

e in

hibi

ted

if th

e an

timic

robi

al c

ompo

und

in th

e bl

ood

reac

hes

the

conc

entra

tions

usu

ally

ach

ieva

ble.

A re

port

of "I

nter

med

iate

" ind

icat

es th

at th

e re

sult

shou

ld b

e co

nsid

ered

eq

uivo

cal,

and,

if th

e m

icro

orga

nism

is n

ot fu

lly s

usce

ptib

le to

alte

rnat

ive,

clin

ical

ly fe

asib

le d

rugs

, the

test

sho

uld

be

repe

ated

. Thi

s ca

tego

ry im

plie

s po

ssib

le c

linic

al a

pplic

abili

ty in

bod

y si

tes

whe

re th

e dr

ug is

phy

siol

ogic

ally

con

cent

rate

d or

in s

ituat

ions

whe

re h

igh

dosa

ge o

f dru

g ca

n be

use

d. T

his

cate

gory

als

o pr

ovid

es a

buf

fer z

one

whi

ch p

reve

nts

smal

l un

cont

rolle

d te

chni

cal f

acto

rs fr

om c

ausi

ng m

ajor

dis

crep

anci

es in

inte

rpre

tatio

n. A

repo

rt of

"Res

ista

nt" i

ndic

ates

that

the

path

ogen

is n

ot li

kely

to b

e in

hibi

ted

if th

e an

timic

robi

al c

ompo

und

in th

e bl

ood

reac

hes

the

conc

entra

tions

usu

ally

ac

hiev

able

; oth

er th

erap

y sh

ould

be

sele

cted

. Qu

ality

Con

trol:

Stan

dard

ized

susc

eptib

ility

test

pro

cedu

res

requ

ire th

e us

e of

labo

rato

ry c

ontro

l mic

roor

gani

sms

to c

ontro

l the

tech

nica

l as

pect

s of

the

labo

rato

ry p

roce

dure

s. S

tand

ard

sulfa

met

hoxa

zole

/trim

etho

prim

pow

der s

houl

d pr

ovid

e th

e fo

llow

ing

rang

e of

val

ues:

M

icro

orga

nism

MIC

(μg/

mL)

Esch

eric

hia

coli

ATCC

259

22

≤ 0.

5/9.

5Ha

emop

hilu

s in

fluen

zaec

AT

CC 4

9247

0.

03/0

.59

– 0.

25/4

.75

Stre

ptoc

occu

s pn

eum

onia

ed

ATCC

496

19

0.12

/2.4

– 1

/19

c.Th

is q

ualit

y co

ntro

l ran

ge is

app

licab

le o

nly

to H

aem

ophi

lus

influ

enza

e AT

CC 4

9247

test

ed b

y br

oth

mic

rodi

lutio

npr

oced

ure

usin

g Ha

emop

hilu

s Te

st M

ediu

m (H

TM).4

d.Th

is q

ualit

y co

ntro

l ran

ge is

app

licab

le to

test

s pe

rform

ed b

y th

e br

oth

mic

rodi

lutio

n m

etho

d on

ly u

sing

cat

ion-

adju

sted

Mue

ller-

Hint

on b

roth

with

2%

to 5

% ly

sed

hors

e bl

ood.

4 Di

ffusi

on T

echn

ique

s:

Quan

titat

ive

met

hods

that

requ

ire m

easu

rem

ent o

f zon

e di

amet

ers

also

pro

vide

repr

oduc

ible

est

imat

es o

f the

sus

cept

ibili

ty

of b

acte

ria to

ant

imic

robi

al c

ompo

unds

. One

suc

h st

anda

rdize

d pr

oced

ure5

requ

ires

the

use

of s

tand

ardi

zed

inoc

ulum

co

ncen

tratio

ns. T

his

proc

edur

e us

es p

aper

dis

ks im

preg

nate

d w

ith 1

.25/

23.7

5 μ

g of

sul

fam

etho

xazo

le/tr

imet

hopr

im to

test

th

e su

scep

tibili

ty o

f mic

roor

gani

sms

to s

ulfa

met

hoxa

zole

/trim

etho

prim

. Re

ports

from

the

labo

rato

ry p

rovi

ding

resu

lts o

f the

sta

ndar

d si

ngle

-dis

k su

scep

tibili

ty te

st w

ith a

1.2

5/23

.75

μg

of

sulfa

met

hoxa

zole

/trim

etho

prim

dis

k sh

ould

be

inte

rpre

ted

acco

rdin

g to

the

follo

win

g cr

iteria

: Fo

r tes

ting

eith

er E

nter

obac

teria

ceae

or H

aem

ophi

lus

influ

enza

ee:

Zone

Dia

met

er (m

m)

Inte

rpre

tatio

n≥

16

Susc

eptib

le (S

)11

– 1

5 In

term

edia

te (I

)≤

10

Resi

stan

t (R)

e.Th

ese

zone

dia

met

er s

tand

ards

are

app

licab

le o

nly

for d

isk

diffu

sion

test

ing

with

Hae

mop

hilu

s in

fluen

zae

and

Haem

ophi

lus

Test

Med

ium

(HTM

).5

Whe

n te

stin

g St

rept

ococ

cus

pneu

mon

iaef

:Zo

ne D

iam

eter

(mm

) In

terp

reta

tion

≥ 19

Su

scep

tible

(S)

16 –

18

Inte

rmed

iate

(I)

≤ 15

Re

sist

ant (

R)f.

Thes

e zo

ne d

iam

eter

inte

rpre

tativ

e st

anda

rds

are

appl

icab

le o

nly

to te

sts

perfo

rmed

usi

ng M

uelle

r-Hi

nton

aga

rsu

pple

men

ted

with

5%

def

ibrin

ated

she

ep b

lood

whe

n in

cuba

ted

in 5

% C

O 2.5

In

terp

reta

tion

shou

ld b

e as

sta

ted

abov

e fo

r res

ults

usi

ng d

ilutio

n te

chni

ques

. Int

erpr

etat

ion

invo

lves

cor

rela

tion

of th

e di

amet

er o

btai

ned

in th

e di

sk te

st w

ith th

e M

IC fo

r sul

fam

etho

xazo

le/tr

imet

hopr

im.

Qual

ity C

ontro

l: As

with

sta

ndar

dize

d di

lutio

n te

chni

ques

, diff

usio

n m

etho

ds re

quire

the

use

of la

bora

tory

con

trol m

icro

orga

nism

s th

at a

re

used

to c

ontro

l the

tech

nica

l asp

ects

of t

he la

bora

tory

pro

cedu

res.

For

the

diffu

sion

tech

niqu

e, th

e 1.

25/2

3.75

μg

sulfa

met

hoxa

zole

/trim

etho

prim

dis

k* s

houl

d pr

ovid

e th

e fo

llow

ing

zone

dia

met

ers

in th

ese

labo

rato

ry te

st q

ualit

y co

ntro

l st

rain

s:M

icro

orga

nism

Zone

Dia

met

er R

ange

s (m

m)

Esch

eric

hia

coli

AT

CC 2

5922

23

–29

Haem

ophi

lus

influ

enza

eg

ATCC

492

47

24–3

2 St

rept

ococ

cus

pneu

mon

iaeh

AT

CC 4

9619

20

–28

* M

uelle

r-Hi

nton

aga

r sho

uld

be c

heck

ed fo

r exc

essi

ve le

vels

of t

hym

idin

e or

thym

ine.

To

dete

rmin

e w

heth

erM

uelle

r-Hi

nton

med

ium

has

suf

ficie

ntly

low

leve

ls o

f thy

mid

ine

and

thym

ine,

an

Ente

roco

ccus

faec

alis

(ATC

C 29

212

or

ATCC

331

86) m

ay b

e te

sted

with

sul

fam

etho

xazo

le/tr

imet

hopr

im d

isks

. A zo

ne o

f inh

ibiti

on ≥

20 m

m th

at is

ess

entia

lly

free

of fi

ne c

olon

ies

indi

cate

s a

suffi

cien

tly lo

w le

vel o

f thy

mid

ine

and

thym

ine.

g.

This

qua

lity

cont

rol r

ange

is a

pplic

able

onl

y to

Hae

mop

hilu

s in

fluen

zae

ATCC

492

47 te

sted

by

a di

sk d

iffus

ion

proc

edur

eus

ing

Haem

ophi

lus

Test

Med

ium

(HTM

).5h.

This

qua

lity

cont

rol r

ange

is a

pplic

able

onl

y to

test

s pe

rform

ed b

y di

sk d

iffus

ion

usin

g M

uelle

r-Hi

nton

aga

r sup

plem

ente

dw

ith 5

% d

efib

rinat

ed s

heep

blo

od w

hen

incu

bate

d in

5%

CO 2

.5IN

DICA

TION

S AN

D US

AGE

To re

duce

the

deve

lopm

ent o

f dru

g-re

sist

ant b

acte

ria a

nd m

aint

ain

the

effe

ctiv

enes

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

oral

sus

pens

ion

and

othe

r ant

ibac

teria

l dru

gs, s

ulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

shou

ld b

e us

ed o

nly

to

treat

or p

reve

nt in

fect

ions

that

are

pro

ven

or s

trong

ly s

uspe

cted

to b

e ca

used

by

susc

eptib

le b

acte

ria. W

hen

cultu

re a

nd

susc

eptib

ility

info

rmat

ion

are

avai

labl

e, th

ey s

houl

d be

con

side

red

in s

elec

ting

or m

odify

ing

antib

acte

rial t

hera

py. I

n th

e ab

senc

e of

suc

h da

ta, l

ocal

epi

dem

iolo

gy a

nd s

usce

ptib

ility

pat

tern

s m

ay c

ontri

bute

to e

mpi

ric s

elec

tion

of th

erap

y.Ur

inar

y Tr

act I

nfec

tions

: For

the

treat

men

t of u

rinar

y tra

ct in

fect

ions

due

to s

usce

ptib

le s

train

s of

the

follo

win

g or

gani

sms:

Es

cher

ichi

a co

li, K

lebs

iella

spe

cies

, Ent

erob

acte

r spe

cies

, Mor

gane

lla m

orga

nii,

Prot

eus

mira

bilis

and

Pro

teus

vul

garis

. It i

s re

com

men

ded

that

initi

al e

piso

des

of u

ncom

plic

ated

urin

ary

tract

infe

ctio

ns b

e tre

ated

with

a s

ingl

e ef

fect

ive

antib

acte

rial

agen

t rat

her t

han

the

com

bina

tion.

Acut

e Ot

itis

Med

ia: F

or th

e tre

atm

ent o

f acu

te o

titis

med

ia in

ped

iatri

c pa

tient

s du

e to

sus

cept

ible

stra

ins

of S

trept

ococ

cus

pneu

mon

iae

or H

aem

ophi

lus

influ

enza

e w

hen

in th

e ju

dgm

ent o

f the

phy

sici

an s

ulfa

met

hoxa

zole

and

trim

etho

prim

offe

rs

som

e ad

vant

age

over

the

use

of o

ther

ant

imic

robi

al a

gent

s. T

o da

te, t

here

are

lim

ited

data

on

the

safe

ty o

f rep

eate

d us

e of

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im in

ped

iatri

c pa

tient

s un

der t

wo

year

s of

age

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

not

in

dica

ted

for p

roph

ylac

tic o

r pro

long

ed a

dmin

istra

tion

in o

titis

med

ia a

t any

age

.Ac

ute

Exac

erba

tions

of C

hron

ic B

ronc

hitis

in A

dults

: For

the

treat

men

t of a

cute

exa

cerb

atio

ns o

f chr

onic

bro

nchi

tis d

ue to

su

scep

tible

stra

ins

of S

trept

ococ

cus

pneu

mon

iae

or H

aem

ophi

lus

influ

enza

e w

hen

in th

e ju

dgm

ent o

f the

phy

sici

an

sulfa

met

hoxa

zole

and

trim

etho

prim

offe

rs s

ome

adva

ntag

e ov

er th

e us

e of

a s

ingl

e an

timic

robi

al a

gent

.Sh

igel

losi

s: F

or th

e tre

atm

ent o

f ent

eriti

s ca

used

by

susc

eptib

le s

train

s of

Shi

gella

flex

neri

and

Shig

ella

son

nei w

hen

antib

acte

rial t

hera

py is

indi

cate

d.Pn

eum

ocys

tis C

arin

ii Pn

eum

onia

: For

the

treat

men

t of d

ocum

ente

d Pn

eum

ocys

tis c

arin

ii pn

eum

onia

and

for p

roph

ylax

is

agai

nst P

neum

ocys

tis c

arin

ii pn

eum

onia

in in

divi

dual

s w

ho a

re im

mun

osup

pres

sed

and

cons

ider

ed to

be

at a

n in

crea

sed

risk

of d

evel

opin

g Pn

eum

ocys

tis c

arin

ii pn

eum

onia

.Tr

avel

ers’

Dia

rrhe

a In

Adu

lts: F

or th

e tre

atm

ent o

f tra

vele

rs’ d

iarr

hea

due

to s

usce

ptib

le s

train

s of

ent

erot

oxig

enic

E. c

oli.

CONT

RAIN

DICA

TION

SSu

lfam

etho

xazo

le a

nd tr

imet

hopr

im is

con

train

dica

ted

in p

atie

nts

with

a k

now

n hy

pers

ensi

tivity

to tr

imet

hopr

im o

r su

lfona

mid

es, i

n pa

tient

s w

ith a

his

tory

of d

rug-

indu

ced

imm

une

thro

mbo

cyto

peni

a w

ith u

se o

f trim

etho

prim

and

/or

sulfo

nam

ides

, and

in p

atie

nts

with

doc

umen

ted

meg

alob

last

ic a

nem

ia d

ue to

fola

te d

efic

ienc

y. S

ulfa

met

hoxa

zole

and

tri

met

hopr

im is

als

o co

ntra

indi

cate

d in

pre

gnan

t pat

ient

s an

d nu

rsin

g m

othe

rs, b

ecau

se s

ulfo

nam

ides

pas

s th

e pl

acen

ta

and

are

excr

eted

in th

e m

ilk a

nd m

ay c

ause

ker

nict

erus

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

con

train

dica

ted

in p

edia

tric

patie

nts

less

than

2 m

onth

s of

age

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

als

o co

ntra

indi

cate

d in

pat

ient

s w

ith m

arke

d he

patic

dam

age

or w

ith s

ever

e re

nal i

nsuf

ficie

ncy

whe

n re

nal f

unct

ion

stat

us c

anno

t be

mon

itore

d.W

ARNI

NGS

FATA

LITI

ES A

SSOC

IATE

D W

ITH

THE

ADM

INIS

TRAT

ION

OF S

ULFO

NAM

IDES

, ALT

HOUG

H RA

RE, H

AVE

OCCU

RRED

DUE

TO

SEV

ERE

REAC

TION

S, IN

CLUD

ING

STEV

ENS-

JOHN

SON

SYND

ROM

E, T

OXIC

EPI

DERM

AL N

ECRO

LYSI

S, F

ULM

INAN

T HE

PATI

C NE

CROS

IS, A

GRAN

ULOC

YTOS

IS, A

PLAS

TIC

ANEM

IA A

ND O

THER

BLO

OD D

YSCR

ASIA

S.SU

LFON

AMID

ES, I

NCLU

DING

SUL

FONA

MID

E-CO

NTAI

NING

PRO

DUCT

S SU

CH A

S SU

LFAM

ETHO

XAZO

LE/T

RIM

ETHO

PRIM

, SH

OULD

BE

DISC

ONTI

NUED

AT

THE

FIRS

T AP

PEAR

ANCE

OF

SKIN

RAS

H OR

ANY

SIG

N OF

ADV

ERSE

REA

CTIO

N. In

rare

in

stan

ces,

a s

kin

rash

may

be

follo

wed

by

a m

ore

seve

re re

actio

n, s

uch

as S

teve

ns-J

ohns

on s

yndr

ome,

toxi

c ep

ider

mal

ne

crol

ysis

, hep

atic

nec

rosi

s, a

nd s

erio

us b

lood

dis

orde

rs (s

ee P

RECA

UTIO

NS).

Clin

ical

sig

ns, s

uch

as ra

sh, s

ore

thro

at,

feve

r, ar

thra

lgia

, pal

lor,

purp

ura

or ja

undi

ce m

ay b

e ea

rly in

dica

tions

of s

erio

us re

actio

ns.

Coug

h, s

hortn

ess

of b

reat

h, a

nd p

ulm

onar

y in

filtra

tes

are

hype

rsen

sitiv

ity re

actio

ns o

f the

resp

irato

ry tr

act t

hat h

ave

been

repo

rted

in a

ssoc

iatio

n w

ith s

ulfo

nam

ide

treat

men

t.Th

rom

bocy

tope

nia

Sulfa

met

hoxa

zole

/trim

etho

prim

-indu

ced

thro

mbo

cyto

peni

a m

ay b

e an

imm

une-

med

iate

d di

sord

er. S

ever

e ca

ses

of

thro

mbo

cyto

peni

a th

at a

re fa

tal o

r life

thre

aten

ing

have

bee

n re

porte

d. T

hrom

bocy

tope

nia

usua

lly re

solv

es w

ithin

a w

eek

upon

dis

cont

inua

tion

of s

ulfa

met

hoxa

zole

/trim

etho

prim

.Th

e su

lfona

mid

es s

houl

d no

t be

used

for t

he tr

eatm

ent o

f gro

up A

β-h

emol

ytic

stre

ptoc

occa

l inf

ectio

ns. I

n an

est

ablis

hed

infe

ctio

n, th

ey w

ill n

ot e

radi

cate

the

stre

ptoc

occu

s an

d, th

eref

ore,

will

not

pre

vent

seq

uela

e su

ch a

s rh

eum

atic

feve

r.Cl

ostri

dium

diff

icile

ass

ocia

ted

diar

rhea

(CDA

D) h

as b

een

repo

rted

with

use

of n

early

all

antib

acte

rial a

gent

s, in

clud

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

, and

may

rang

e in

sev

erity

from

mild

dia

rrhe

a to

fata

l col

itis.

Tre

atm

ent w

ith

antib

acte

rial a

gent

s al

ters

the

norm

al fl

ora

of th

e co

lon

lead

ing

to o

verg

row

th o

f C. d

iffic

ile.

C. d

iffic

ile p

rodu

ces

toxi

ns A

and

B w

hich

con

tribu

te to

the

deve

lopm

ent o

f CDA

D. H

yper

toxi

n pr

oduc

ing

stra

ins

of C

. di

ffici

le c

ause

incr

ease

d m

orbi

dity

and

mor

talit

y, a

s th

ese

infe

ctio

ns c

an b

e re

fract

ory

to a

ntim

icro

bial

ther

apy

and

may

re

quire

col

ecto

my.

CDA

D m

ust b

e co

nsid

ered

in a

ll pa

tient

s w

ho p

rese

nt w

ith d

iarr

hea

follo

win

g an

tibio

tic u

se. C

aref

ul

med

ical

his

tory

is n

eces

sary

sin

ce C

DAD

has

been

repo

rted

to o

ccur

ove

r tw

o m

onth

s af

ter t

he a

dmin

istra

tion

of

antib

acte

rial a

gent

s.If

CDAD

is s

uspe

cted

or c

onfir

med

, ong

oing

ant

ibio

tic u

se n

ot d

irect

ed a

gain

st C

. diff

icile

may

nee

d to

be

disc

ontin

ued.

Ap

prop

riate

flui

d an

d el

ectro

lyte

man

agem

ent,

prot

ein

supp

lem

enta

tion,

ant

ibio

tic tr

eatm

ent o

f C. d

iffic

ile, a

nd s

urgi

cal

eval

uatio

n sh

ould

be

inst

itute

d as

clin

ical

ly in

dica

ted.

PREC

AUTI

ONS

Gene

ral

Pres

crib

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

in th

e ab

senc

e of

a p

rove

n or

stro

ngly

sus

pect

ed b

acte

rial

infe

ctio

n or

a p

roph

ylac

tic in

dica

tion

is u

nlik

ely

to p

rovi

de b

enef

it to

the

patie

nt a

nd in

crea

ses

the

risk

of th

e de

velo

pmen

t of

dru

g-re

sist

ant b

acte

ria.

Sulfa

met

hoxa

zole

and

trim

etho

prim

sho

uld

be g

iven

with

cau

tion

to p

atie

nts

with

impa

ired

rena

l or h

epat

ic fu

nctio

n, to

th

ose

with

pos

sibl

e fo

late

def

icie

ncy

(e.g

., th

e el

derly

, chr

onic

alc

ohol

ics,

pat

ient

s re

ceiv

ing

antic

onvu

lsan

t the

rapy

, pa

tient

s w

ith m

alab

sorp

tion

synd

rom

e, a

nd p

atie

nts

in m

alnu

tritio

n st

ates

) and

to th

ose

with

sev

ere

alle

rgie

s or

bro

nchi

al

asth

ma.

In g

luco

se-6

-pho

spha

te d

ehyd

roge

nase

def

icie

nt in

divi

dual

s, h

emol

ysis

may

occ

ur. T

his

reac

tion

is fr

eque

ntly

do

se-r

elat

ed (s

ee C

LINI

CAL

PHAR

MAC

OLOG

Y an

d DO

SAGE

AND

ADM

INIS

TRAT

ION)

.Ca

ses

of h

ypog

lyce

mia

in n

on-d

iabe

tic p

atie

nts

treat

ed w

ith s

ulfa

met

hoxa

zole

and

trim

etho

prim

are

see

n ra

rely

, usu

ally

oc

curr

ing

afte

r a fe

w d

ays

of th

erap

y. P

atie

nts

with

rena

l dys

func

tion,

live

r dis

ease

, mal

nutri

tion

or th

ose

rece

ivin

g hi

gh

dose

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re p

artic

ular

ly a

t ris

k.

Hem

atol

ogic

al c

hang

es in

dica

tive

of fo

lic a

cid

defic

ienc

y m

ay o

ccur

in e

lder

ly p

atie

nts

or in

pat

ient

s w

ith p

reex

istin

g fo

lic

acid

def

icie

ncy

or k

idne

y fa

ilure

. The

se e

ffect

s ar

e re

vers

ible

by

folin

ic a

cid

ther

apy.

Tr

imet

hopr

im h

as b

een

note

d to

impa

ir ph

enyl

alan

ine

met

abol

ism

, but

this

is o

f no

sign

ifica

nce

in p

heny

lket

onur

ic p

atie

nts

on a

ppro

pria

te d

ieta

ry re

stric

tion.

As

with

all

drug

s co

ntai

ning

sul

fona

mid

es, c

autio

n is

adv

isab

le in

pat

ient

s w

ith p

orph

yria

or t

hyro

id d

ysfu

nctio

n.Us

e in

the

Trea

tmen

t of a

nd P

roph

ylax

is fo

r Pne

umoc

ystis

Car

inii

Pneu

mon

ia in

Pat

ient

s w

ith A

cqui

red

Imm

unod

efic

ienc

y Sy

ndro

me

(AID

S): A

IDS

patie

nts

may

not

tole

rate

or r

espo

nd to

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im in

th

e sa

me

man

ner a

s no

n-AI

DS p

atie

nts.

The

inci

denc

e of

sid

e ef

fect

s, p

artic

ular

ly ra

sh, f

ever

, leu

kope

nia

and

elev

ated

am

inot

rans

fera

se (t

rans

amin

ase)

val

ues,

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im th

erap

y in

AID

S pa

tient

s w

ho a

re b

eing

tre

ated

for P

neum

ocys

tis c

arin

ii pn

eum

onia

has

bee

n re

porte

d to

be

grea

tly in

crea

sed

com

pare

d w

ith th

e in

cide

nce

norm

ally

ass

ocia

ted

with

the

use

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

in n

on-A

IDS

patie

nts.

The

inci

denc

e of

hy

perk

alem

ia a

ppea

rs to

be

incr

ease

d in

AID

S pa

tient

s re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

. Adv

erse

effe

cts

are

gene

rally

less

sev

ere

in p

atie

nts

rece

ivin

g su

lfam

etho

xazo

le a

nd tr

imet

hopr

im fo

r pro

phyl

axis

. A h

isto

ry o

f mild

into

lera

nce

to s

ulfa

met

hoxa

zole

and

trim

etho

prim

in A

IDS

patie

nts

does

not

app

ear t

o pr

edic

t int

oler

ance

of s

ubse

quen

t sec

onda

ry

prop

hyla

xis.

6 Ho

wev

er, i

f a p

atie

nt d

evel

ops

skin

rash

or a

ny s

ign

of a

dver

se re

actio

n, th

erap

y w

ith s

ulfa

met

hoxa

zole

and

tri

met

hopr

im s

houl

d be

reev

alua

ted

(see

WAR

NING

S).

High

dos

age

of tr

imet

hopr

im, a

s us

ed in

pat

ient

s w

ith P

neum

ocys

tis c

arin

ii pn

eum

onia

, ind

uces

a p

rogr

essi

ve b

ut

reve

rsib

le in

crea

se o

f ser

um p

otas

sium

con

cent

ratio

ns in

a s

ubst

antia

l num

ber o

f pat

ient

s. E

ven

treat

men

t with

re

com

men

ded

dose

s m

ay c

ause

hyp

erka

lem

ia w

hen

trim

etho

prim

is a

dmin

iste

red

to p

atie

nts

with

und

erly

ing

diso

rder

s of

po

tass

ium

met

abol

ism

, with

rena

l ins

uffic

ienc

y, o

r if d

rugs

kno

wn

to in

duce

hyp

erka

lem

ia a

re g

iven

con

com

itant

ly. C

lose

m

onito

ring

of s

erum

pot

assi

um is

war

rant

ed in

thes

e pa

tient

s.

Durin

g tre

atm

ent,

adeq

uate

flui

d in

take

and

urin

ary

outp

ut s

houl

d be

ens

ured

to p

reve

nt c

ryst

allu

ria. P

atie

nts

who

are

"s

low

ace

tyla

tors

" may

be

mor

e pr

one

to id

iosy

ncra

tic re

actio

ns to

sul

fona

mid

es.

24.625"

2.000" 1.813" 1.750" 1.688" 1.688" 1.750" 1.750" 1.750" 1.750" 1.688" 1.688" 1.750" 1.813" 1.750"

4.12

5"



Trimethoprim OS, USPGrape Flavor



IMPRINTAREA

RESEALAREABLACK PMS 321

GREENPMS 2613PURPLE

Base Label

50383-824-163 9

Grape Flavor

Grape Flavor



Rx only

16 fl oz (473 mL)

Rev. 824:07 7/11

NDC 50383-824-16

4.125"

4.125"


16 fl oz (473 mL)





Book Placement1.813" 2.000"

0.313"


APPROVAL SIGNATURE/DATE:

APPROVED

REVISE AND RE-PROOF

PLATINUM PRESS FAX:(469)733-1510

GRAPHICS PROOFSize:

Rev:

4.125” x 4.125” CopyPosition

8

Co

py

#4

#4

5 09/15/11 TA6 09/23/11 TA7 09/29/11 TA8 10/17/11 MC

Rev.# Date Artist

PHARMACAL PHARMACAL






Front

Cover(Page #1)

Page #20 Page #21 Page #22 Page #23 Page #24 Page #25 Page #26 Page #27 Page #28Page #16 Page #17 Page #18 Page #19


APPROVAL SIGNATURE

APPROVED

REVISE AND RE-PROOF


GRAPHICS PROOFSize:

Rev:


Co

py

#4

#4BLACK PMS 321

GREENPMS 2613PURPLE

4.12

5"

24.625"

1.750" 1.813" 1.750" 1.688" 1.688" 1.750" 1.750" 1.750" 1.750" 1.688" 1.688" 1.750" 1.813" 2.000"

Grape Flavor



16 fl oz (473 mL)





Lift HerePHARMACAL

Info

rmat

ion

for P

atie

nts

Patie

nts

shou

ld b

e co

unse

led

that

ant

ibac

teria

l dru

gs in

clud

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

shou

ld

only

be

used

to tr

eat b

acte

rial i

nfec

tions

. The

y do

not

trea

t vira

l inf

ectio

ns (e

.g.,

the

com

mon

col

d). W

hen

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

is p

resc

ribed

to tr

eat a

bac

teria

l inf

ectio

n, p

atie

nts

shou

ld b

e to

ld th

at

alth

ough

it is

com

mon

to fe

el b

ette

r ear

ly in

the

cour

se o

f the

rapy

, the

med

icat

ion

shou

ld b

e ta

ken

exac

tly a

s di

rect

ed.

Skip

ping

dos

es o

r not

com

plet

ing

the

full

cour

se o

f the

rapy

may

(1) d

ecre

ase

the

effe

ctiv

enes

s of

the

imm

edia

te tr

eatm

ent

and

(2) i

ncre

ase

the

likel

ihoo

d th

at b

acte

ria w

ill d

evel

op re

sist

ance

and

will

not

be

treat

able

by

sulfa

met

hoxa

zole

and

tri

met

hopr

im o

ral s

uspe

nsio

n or

oth

er a

ntib

acte

rial d

rugs

in th

e fu

ture

.Pa

tient

s sh

ould

be

inst

ruct

ed to

mai

ntai

n an

ade

quat

e flu

id in

take

in o

rder

to p

reve

nt c

ryst

allu

ria a

nd s

tone

form

atio

n.Di

arrh

ea is

a c

omm

on p

robl

em c

ause

d by

ant

ibio

tics

whi

ch u

sual

ly e

nds

whe

n th

e an

tibio

tic is

dis

cont

inue

d. S

omet

imes

af

ter s

tarti

ng tr

eatm

ent w

ith a

ntib

iotic

s, p

atie

nts

can

deve

lop

wat

ery

and

bloo

dy s

tool

s (w

ith a

nd w

ithou

t sto

mac

h cr

amps

an

d fe

ver)

eve

n as

late

as

two

or m

ore

mon

ths

afte

r hav

ing

take

n th

e la

st d

ose

of th

e an

tibio

tic. I

f thi

s oc

curs

, pat

ient

s sh

ould

con

tact

thei

r phy

sici

an a

s so

on a

s po

ssib

le.

Labo

rato

ry T

ests

Com

plet

e bl

ood

coun

ts s

houl

d be

don

e fre

quen

tly in

pat

ient

s re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

; if a

sig

nific

ant

redu

ctio

n in

the

coun

t of a

ny fo

rmed

blo

od e

lem

ent i

s no

ted,

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im s

houl

d be

dis

cont

inue

d.

Urin

alys

is w

ith c

aref

ul m

icro

scop

ic e

xam

inat

ion

and

rena

l fun

ctio

n te

sts

shou

ld b

e pe

rform

ed d

urin

g th

erap

y, p

artic

ular

ly

for t

hose

pat

ient

s w

ith im

paire

d re

nal f

unct

ion.

Drug

Inte

ract

ions

In e

lder

ly p

atie

nts

conc

urre

ntly

rece

ivin

g ce

rtain

diu

retic

s, p

rimar

ily th

iazid

es, a

n in

crea

sed

inci

denc

e of

thro

mbo

cyto

peni

a w

ith p

urpu

ra h

as b

een

repo

rted.

It

has

been

repo

rted

that

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay p

rolo

ng th

e pr

othr

ombi

n tim

e in

pat

ient

s w

ho a

re

rece

ivin

g th

e an

ticoa

gula

nt w

arfa

rin. T

his

inte

ract

ion

shou

ld b

e ke

pt in

min

d w

hen

sulfa

met

hoxa

zole

and

trim

etho

prim

is

give

n to

pat

ient

s al

read

y on

ant

icoa

gula

nt th

erap

y, a

nd th

e co

agul

atio

n tim

e sh

ould

be

reas

sess

ed.

Sulfa

met

hoxa

zole

and

trim

etho

prim

may

inhi

bit t

he h

epat

ic m

etab

olis

m o

f phe

nyto

in. S

ulfa

met

hoxa

zole

and

trim

etho

prim

, gi

ven

at a

com

mon

clin

ical

dos

age,

incr

ease

d th

e ph

enyt

oin

half-

life

by 3

9% a

nd d

ecre

ased

the

phen

ytoi

n m

etab

olic

cle

aran

ce

rate

by

27%

. Whe

n ad

min

iste

ring

thes

e dr

ugs

conc

urre

ntly

, one

sho

uld

be a

lert

for p

ossi

ble

exce

ssiv

e ph

enyt

oin

effe

ct.

Sulfo

nam

ides

can

als

o di

spla

ce m

etho

trexa

te fr

om p

lasm

a pr

otei

n bi

ndin

g si

tes

and

can

com

pete

with

the

rena

l tra

nspo

rt of

met

hotre

xate

, thu

s in

crea

sing

free

met

hotre

xate

con

cent

ratio

ns.

Ther

e ha

ve b

een

repo

rts o

f mar

ked

but r

ever

sibl

e ne

phro

toxi

city

with

coa

dmin

istra

tion

of s

ulfa

met

hoxa

zole

and

tri

met

hopr

im a

nd c

yclo

spor

ine

in re

nal t

rans

plan

t rec

ipie

nts.

In

crea

sed

digo

xin

bloo

d le

vels

can

occ

ur w

ith c

onco

mita

nt s

ulfa

met

hoxa

zole

and

trim

etho

prim

ther

apy,

esp

ecia

lly in

el

derly

pat

ient

s. S

erum

dig

oxin

leve

ls s

houl

d be

mon

itore

d.

Incr

ease

d su

lfam

etho

xazo

le b

lood

leve

ls m

ay o

ccur

in p

atie

nts

who

are

als

o re

ceiv

ing

indo

met

haci

n.

Occa

sion

al re

ports

sug

gest

that

pat

ient

s re

ceiv

ing

pyrim

etha

min

e as

mal

aria

pro

phyl

axis

in d

oses

exc

eedi

ng 2

5 m

g w

eekl

y m

ay d

evel

op m

egal

obla

stic

ane

mia

if s

ulfa

met

hoxa

zole

and

trim

etho

prim

is p

resc

ribed

. Th

e ef

ficac

y of

tric

yclic

ant

idep

ress

ants

can

dec

reas

e w

hen

coad

min

iste

red

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im.

Like

oth

er s

ulfo

nam

ide-

cont

aini

ng d

rugs

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im p

oten

tiate

s th

e ef

fect

of o

ral h

ypog

lyce

mic

s.

In th

e lit

erat

ure,

a s

ingl

e ca

se o

f tox

ic d

eliri

um h

as b

een

repo

rted

afte

r con

com

itant

inta

ke o

f su

lfam

etho

xazo

le/tr

imet

hopr

im a

nd a

man

tadi

ne.

In th

e lit

erat

ure,

thre

e ca

ses

of h

yper

kale

mia

in e

lder

ly p

atie

nts

have

bee

n re

porte

d af

ter c

onco

mita

nt in

take

of

sulfa

met

hoxa

zole

/trim

etho

prim

and

an

angi

oten

sin

conv

ertin

g en

zym

e in

hibi

tor.7

,8

Drug

/Lab

orat

ory

Test

Inte

ract

ions

Sulfa

met

hoxa

zole

and

trim

etho

prim

, spe

cific

ally

the

trim

etho

prim

com

pone

nt, c

an in

terfe

re w

ith a

ser

um m

etho

trexa

te

assa

y as

det

erm

ined

by

the

com

petit

ive

bind

ing

prot

ein

tech

niqu

e (C

BPA)

whe

n a

bact

eria

l dih

ydro

fola

te re

duct

ase

is u

sed

as th

e bi

ndin

g pr

otei

n. N

o in

terfe

renc

e oc

curs

, how

ever

, if m

etho

trexa

te is

mea

sure

d by

a ra

dioi

mm

unoa

ssay

(RIA

).Th

e pr

esen

ce o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay a

lso

inte

rfere

with

the

Jaffé

alk

alin

e pi

crat

e re

actio

n as

say

for

crea

tinin

e, re

sulti

ng in

ove

rest

imat

ions

of a

bout

10%

in th

e ra

nge

of n

orm

al v

alue

s.Ca

rcin

ogen

esis

, Mut

agen

esis

, Im

pairm

ent o

f Fer

tility

Carc

inog

enes

is: L

ong-

term

stu

dies

in a

nim

als

to e

valu

ate

carc

inog

enic

pot

entia

l hav

e no

t bee

n co

nduc

ted

with

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im.

Mut

agen

esis

: Bac

teria

l mut

agen

ic s

tudi

es h

ave

not b

een

perfo

rmed

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im in

co

mbi

natio

n. T

rimet

hopr

im w

as d

emon

stra

ted

to b

e no

nmut

agen

ic in

the

Ames

ass

ay. N

o ch

rom

osom

al d

amag

e w

as

obse

rved

in h

uman

leuk

ocyt

es c

ultu

red

in v

itro

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

lone

or i

n co

mbi

natio

n; th

e co

ncen

tratio

ns u

sed

exce

eded

blo

od le

vels

of t

hese

com

poun

ds fo

llow

ing

ther

apy

with

sul

fam

etho

xazo

le a

nd

trim

etho

prim

. Obs

erva

tions

of l

euko

cyte

s ob

tain

ed fr

om p

atie

nts

treat

ed w

ith s

ulfa

met

hoxa

zole

and

trim

etho

prim

reve

aled

no

chr

omos

omal

abn

orm

aliti

es.

Impa

irmen

t of F

ertil

ity: N

o ad

vers

e ef

fect

s on

ferti

lity

or g

ener

al re

prod

uctiv

e pe

rform

ance

wer

e ob

serv

ed in

rats

giv

en

oral

dos

ages

as

high

as

350

mg/

kg/d

ay s

ulfa

met

hoxa

zole

plu

s 70

mg/

kg/d

ay tr

imet

hopr

im.

Preg

nanc

yTe

rato

geni

c Ef

fect

s: P

regn

ancy

Cat

egor

y C.

In ra

ts, o

ral d

oses

of 5

33 m

g/kg

or 2

00 m

g/kg

pro

duce

d te

rato

logi

c ef

fect

s m

anife

sted

mai

nly

as c

left

pala

tes.

Th

e hi

ghes

t dos

e w

hich

did

not

cau

se c

left

pala

tes

in ra

ts w

as 5

12 m

g/kg

sul

fam

etho

xazo

le o

r 192

mg/

kg tr

imet

hopr

im

whe

n ad

min

iste

red

sepa

rate

ly. I

n tw

o st

udie

s in

rats

, no

tera

tolo

gy w

as o

bser

ved

whe

n 51

2 m

g/kg

of s

ulfa

met

hoxa

zole

w

as u

sed

in c

ombi

natio

n w

ith 1

28 m

g/kg

of t

rimet

hopr

im. I

n on

e st

udy,

how

ever

, cle

ft pa

late

s w

ere

obse

rved

in o

ne li

tter

out o

f 9 w

hen

355

mg/

kg o

f sul

fam

etho

xazo

le w

as u

sed

in c

ombi

natio

n w

ith 8

8 m

g/kg

of t

rimet

hopr

im.

In s

ome

rabb

it st

udie

s, a

n ov

eral

l inc

reas

e in

feta

l los

s (d

ead

and

reso

rbed

and

mal

form

ed c

once

ptus

es) w

as a

ssoc

iate

d w

ith d

oses

of t

rimet

hopr

im 6

tim

es th

e hu

man

ther

apeu

tic d

ose.

Whi

le th

ere

are

no la

rge,

wel

l-con

trolle

d st

udie

s on

the

use

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

in p

regn

ant w

omen

, Br

umfit

t and

Pur

sell,

9 in

a re

trosp

ectiv

e st

udy,

repo

rted

the

outc

ome

of 1

86 p

regn

anci

es d

urin

g w

hich

the

mot

her r

ecei

ved

eith

er p

lace

bo o

r sul

fam

etho

xazo

le a

nd tr

imet

hopr

im. T

he in

cide

nce

of c

onge

nita

l abn

orm

aliti

es w

as 4

.5%

(3 o

f 66)

in

thos

e w

ho re

ceiv

ed p

lace

bo a

nd 3

.3%

(4 o

f 120

) in

thos

e re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

. The

re w

ere

no

abno

rmal

ities

in th

e 10

chi

ldre

n w

hose

mot

hers

rece

ived

the

drug

dur

ing

the

first

trim

este

r. In

a s

epar

ate

surv

ey, B

rum

fitt

and

Purs

ell a

lso

foun

d no

con

geni

tal a

bnor

mal

ities

in 3

5 ch

ildre

n w

hose

mot

hers

had

rece

ived

ora

l sul

fam

etho

xazo

le a

nd

trim

etho

prim

at t

he ti

me

of c

once

ptio

n or

sho

rtly

ther

eafte

r.Be

caus

e su

lfam

etho

xazo

le a

nd tr

imet

hopr

im m

ay in

terfe

re w

ith fo

lic a

cid

met

abol

ism

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

shou

ld b

e us

ed d

urin

g pr

egna

ncy

only

if th

e po

tent

ial b

enef

it ju

stifi

es th

e po

tent

ial r

isk

to th

e fe

tus.

Nont

erat

ogen

ic E

ffect

s: S

ee C

ONTR

AIND

ICAT

IONS

sec

tion.

Nurs

ing

Mot

hers

See

CONT

RAIN

DICA

TION

S se

ctio

n.Pe

diat

ric U

seSu

lfam

etho

xazo

le a

nd tr

imet

hopr

im is

not

reco

mm

ende

d fo

r inf

ants

you

nger

than

2 m

onth

s of

age

(see

INDI

CATI

ONS

AND

USAG

E an

d CO

NTRA

INDI

CATI

ONS

sect

ions

).Ge

riatri

c Us

eCl

inic

al s

tudi

es o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im d

id n

ot in

clud

e su

ffici

ent n

umbe

rs o

f sub

ject

s ag

ed 6

5 an

d ov

er to

de

term

ine

whe

ther

they

resp

ond

diffe

rent

ly fr

om y

oung

er s

ubje

cts.

Ther

e m

ay b

e an

incr

ease

d ris

k of

sev

ere

adve

rse

reac

tions

in e

lder

ly p

atie

nts,

par

ticul

arly

whe

n co

mpl

icat

ing

cond

ition

s ex

ist,

e.g.

, im

paire

d ki

dney

and

/or l

iver

func

tion,

pos

sibl

e fo

late

def

icie

ncy,

or c

onco

mita

nt u

se o

f oth

er d

rugs

. Sev

ere

skin

re

actio

ns, g

ener

alize

d bo

ne m

arro

w s

uppr

essi

on (s

ee W

ARNI

NGS

and

ADVE

RSE

REAC

TION

S se

ctio

ns),

a sp

ecifi

c de

crea

se in

pla

tele

ts (w

ith o

r with

out p

urpu

ra),

and

hype

rkal

emia

are

the

mos

t fre

quen

tly re

porte

d se

vere

adv

erse

re

actio

ns in

eld

erly

pat

ient

s. In

thos

e co

ncur

rent

ly re

ceiv

ing

certa

in d

iure

tics,

prim

arily

thia

zides

, an

incr

ease

d in

cide

nce

of

thro

mbo

cyto

peni

a w

ith p

urpu

ra h

as b

een

repo

rted.

Incr

ease

d di

goxi

n bl

ood

leve

ls c

an o

ccur

with

con

com

itant

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im th

erap

y, e

spec

ially

in e

lder

ly p

atie

nts.

Ser

um d

igox

in le

vels

sho

uld

be m

onito

red.

He

mat

olog

ical

cha

nges

indi

cativ

e of

folic

aci

d de

ficie

ncy

may

occ

ur in

eld

erly

pat

ient

s. T

hese

effe

cts

are

reve

rsib

le b

y fo

linic

aci

d th

erap

y. A

ppro

pria

te d

osag

e ad

just

men

ts s

houl

d be

mad

e fo

r pat

ient

s w

ith im

paire

d ki

dney

func

tion

and

dura

tion

of u

se s

houl

d be

as

shor

t as

poss

ible

to m

inim

ize ri

sks

of u

ndes

ired

reac

tions

(see

DOS

AGE

AND

ADM

INIS

TRAT

ION

sect

ion)

. The

trim

etho

prim

com

pone

nt o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im m

ay c

ause

hyp

erka

lem

ia

whe

n ad

min

iste

red

to p

atie

nts

with

und

erly

ing

diso

rder

s of

pot

assi

um m

etab

olis

m, w

ith re

nal i

nsuf

ficie

ncy

or w

hen

give

n co

ncom

itant

ly w

ith d

rugs

kno

wn

to in

duce

hyp

erka

lem

ia, s

uch

as a

ngio

tens

in c

onve

rting

enz

yme

inhi

bito

rs. C

lose

m

onito

ring

of s

erum

pot

assi

um is

war

rant

ed in

thes

e pa

tient

s. D

isco

ntin

uatio

n of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

treat

men

t is

reco

mm

ende

d to

hel

p lo

wer

pot

assi

um s

erum

leve

ls.

Phar

mac

okin

etic

s pa

ram

eter

s fo

r sul

fam

etho

xazo

le w

ere

sim

ilar f

or g

eria

tric

subj

ects

and

you

nger

adu

lt su

bjec

ts. T

he

mea

n m

axim

um s

erum

trim

etho

prim

con

cent

ratio

n w

as h

ighe

r and

mea

n re

nal c

lear

ance

of t

rimet

hopr

im w

as lo

wer

in

geria

tric

subj

ects

com

pare

d w

ith y

oung

er s

ubje

cts

(see

CLI

NICA

L PH

ARM

ACOL

OGY:

Ger

iatri

c Ph

arm

acok

inet

ics)

.AD

VERS

E RE

ACTI

ONS

The

mos

t com

mon

adv

erse

effe

cts

are

gast

roin

test

inal

dis

turb

ance

s (n

ause

a, v

omiti

ng, a

nore

xia)

and

alle

rgic

ski

n re

actio

ns (s

uch

as ra

sh a

nd u

rtica

ria).

FATA

LITI

ES A

SSOC

IATE

D W

ITH

THE

ADM

INIS

TRAT

ION

OF S

ULFO

NAM

IDES

, AL

THOU

GH R

ARE,

HAV

E OC

CURR

ED D

UE T

O SE

VERE

REA

CTIO

NS, I

NCLU

DING

STE

VENS

-JOH

NSON

SYN

DROM

E,

TOXI

C EP

IDER

MAL

NEC

ROLY

SIS,

FUL

MIN

ANT

HEPA

TIC

NECR

OSIS

, AGR

ANUL

OCYT

OSIS

, APL

ASTI

C AN

EMIA

AND

OT

HER

BLOO

D DY

SCRA

SIAS

(SEE

WAR

NING

S SE

CTIO

N).

Hem

atol

ogic

: Agr

anul

ocyt

osis

, apl

astic

ane

mia

, thr

ombo

cyto

peni

a, le

ukop

enia

, neu

trope

nia,

hem

olyt

ic a

nem

ia,

meg

alob

last

ic a

nem

ia, h

ypop

roth

rom

bine

mia

, met

hem

oglo

bine

mia

, eos

inop

hilia

.Al

lerg

ic R

eact

ions

: Ste

vens

-Joh

nson

syn

drom

e, to

xic

epid

erm

al n

ecro

lysi

s, a

naph

ylax

is, a

llerg

ic m

yoca

rditi

s, e

ryth

ema

mul

tifor

me,

exf

olia

tive

derm

atiti

s, a

ngio

edem

a, d

rug

feve

r, ch

ills,

Hen

och-

Schö

enle

in p

urpu

ra, s

erum

sic

knes

s-lik

e sy

ndro

me,

gen

eral

ized

alle

rgic

reac

tions

, gen

eral

ized

skin

eru

ptio

ns, p

hoto

sens

itivi

ty, c

onju

nctiv

al a

nd s

cler

al in

ject

ion,

pr

uritu

s, u

rtica

ria a

nd ra

sh. I

n ad

ditio

n, p

eria

rterit

is n

odos

a an

d sy

stem

ic lu

pus

eryt

hem

atos

us h

ave

been

repo

rted.

Gast

roin

test

inal

: Hep

atiti

s, (i

nclu

ding

cho

lest

atic

jaun

dice

and

hep

atic

nec

rosi

s), e

leva

tion

of s

erum

tran

sam

inas

e an

d bi

lirub

in,

pseu

dom

embr

anou

s en

tero

colit

is, p

ancr

eatit

is, s

tom

atiti

s, g

loss

itis,

nau

sea,

em

esis

, abd

omin

al p

ain,

dia

rrhe

a, a

nore

xia.

Geni

tour

inar

y: R

enal

failu

re, i

nter

stiti

al n

ephr

itis,

BUN

and

ser

um c

reat

inin

e el

evat

ion,

toxi

c ne

phro

sis

with

olig

uria

and

an

uria

, cry

stal

luria

and

nep

hrot

oxic

ity in

ass

ocia

tion

with

cyc

losp

orin

e.M

etab

olic

and

Nut

ritio

nal:

Hype

rkal

emia

(see

PRE

CAUT

IONS

: Use

in th

e Tr

eatm

ent o

f and

Pro

phyl

axis

for

Pneu

moc

ystis

Car

inii

Pneu

mon

ia in

Pat

ient

s w

ith A

cqui

red

Imm

unod

efic

ienc

y Sy

ndro

me

(AID

S).

Neur

olog

ic: A

sept

ic m

enin

gitis

, con

vuls

ions

, per

iphe

ral n

eurit

is, a

taxi

a, v

ertig

o, ti

nnitu

s, h

eada

che.

Psyc

hiat

ric: H

allu

cina

tions

, dep

ress

ion,

apa

thy,

ner

vous

ness

.En

docr

ine:

The

sul

fona

mid

es b

ear c

erta

in c

hem

ical

sim

ilarit

ies

to s

ome

goitr

ogen

s, d

iure

tics

(ace

tazo

lam

ide

and

the

thia

zides

) and

ora

l hyp

ogly

cem

ic a

gent

s. C

ross

-sen

sitiv

ity m

ay e

xist

with

thes

e ag

ents

. Diu

resi

s an

d hy

pogl

ycem

ia h

ave

occu

rred

rare

ly in

pat

ient

s re

ceiv

ing

sulfo

nam

ides

.M

uscu

losk

elet

al: A

rthra

lgia

and

mya

lgia

. Iso

late

d ca

ses

of rh

abdo

myo

lysi

s ha

ve b

een

repo

rted

with

sul

fam

etho

xazo

le a

nd

trim

etho

prim

, mai

nly

in A

IDS

patie

nts.

Resp

irato

ry: C

ough

, sho

rtnes

s of

bre

ath

and

pulm

onar

y in

filtra

tes

(see

WAR

NING

S).

Mis

cella

neou

s: W

eakn

ess,

fatig

ue, i

nsom

nia.

Post

mar

ketin

g Ex

perie

nce

The

follo

win

g ad

vers

e re

actio

ns h

ave

been

iden

tifie

d du

ring

post

-app

rova

l use

of t

rimet

hopr

im-s

ulfa

met

hoxa

zole

. Bec

ause

th

ese

reac

tions

wer

e re

porte

d vo

lunt

arily

from

a p

opul

atio

n of

unc

erta

in s

ize, i

t is

not p

ossi

ble

to re

liabl

y es

timat

e th

eir

frequ

ency

or e

stab

lish

a ca

usal

rela

tions

hip

to d

rug

expo

sure

:Σ

Thr

ombo

tic th

rom

bocy

tope

nia

purp

ura

Σ Id

iopa

thic

thro

mbo

cyto

peni

c pu

rpur

aOV

ERDO

SAGE

Acut

e: T

he a

mou

nt o

f a s

ingl

e do

se o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im th

at is

eith

er a

ssoc

iate

d w

ith s

ympt

oms

of

over

dosa

ge o

r is

likel

y to

be

life-

thre

aten

ing

has

not b

een

repo

rted.

Sig

ns a

nd s

ympt

oms

of o

verd

osag

e re

porte

d w

ith

sulfo

nam

ides

incl

ude

anor

exia

, col

ic, n

ause

a, v

omiti

ng, d

izzin

ess,

hea

dach

e, d

row

sine

ss a

nd u

ncon

scio

usne

ss. P

yrex

ia,

hem

atur

ia a

nd c

ryst

allu

ria m

ay b

e no

ted.

Blo

od d

yscr

asia

s an

d ja

undi

ce a

re p

oten

tial l

ate

man

ifest

atio

ns o

f ove

rdos

age.

Si

gns

of a

cute

ove

rdos

age

with

trim

etho

prim

incl

ude

naus

ea, v

omiti

ng, d

izzin

ess,

hea

dach

e, m

enta

l dep

ress

ion,

con

fusi

on

and

bone

mar

row

dep

ress

ion.

Ge

nera

l prin

cipl

es o

f tre

atm

ent i

nclu

de th

e in

stitu

tion

of g

astri

c la

vage

or e

mes

is, f

orci

ng o

ral f

luid

s, a

nd th

e ad

min

istra

tion

of in

trave

nous

flui

ds if

urin

e ou

tput

is lo

w a

nd re

nal f

unct

ion

is n

orm

al. A

cidi

ficat

ion

of th

e ur

ine

will

incr

ease

rena

l el

imin

atio

n of

trim

etho

prim

. The

pat

ient

sho

uld

be m

onito

red

with

blo

od c

ount

s an

d ap

prop

riate

blo

od c

hem

istri

es,

incl

udin

g el

ectro

lyte

s. If

a s

igni

fican

t blo

od d

yscr

asia

or j

aund

ice

occu

rs, s

peci

fic th

erap

y sh

ould

be

inst

itute

d fo

r the

se

com

plic

atio

ns. P

erito

neal

dia

lysi

s is

not

effe

ctiv

e an

d he

mod

ialy

sis

is o

nly

mod

erat

ely

effe

ctiv

e in

elim

inat

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

.Ch

roni

c: U

se o

f sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

t hig

h do

ses

and/

or fo

r ext

ende

d pe

riods

of t

ime

may

cau

se b

one

mar

row

dep

ress

ion

man

ifest

ed a

s th

rom

bocy

tope

nia,

leuk

open

ia a

nd/o

r meg

alob

last

ic a

nem

ia. I

f sig

ns o

f bon

e m

arro

w

depr

essi

on o

ccur

, the

pat

ient

sho

uld

be g

iven

leuc

ovor

in 5

to 1

5 m

g da

ily u

ntil

norm

al h

emat

opoi

esis

is re

stor

ed.

DOSA

GE A

ND A

DMIN

ISTR

ATIO

NNo

t rec

omm

ende

d fo

r use

in p

edia

tric

patie

nts

less

than

2 m

onth

s of

age

.Ur

inar

y Tr

act I

nfec

tions

and

Shi

gello

sis

in A

dults

and

Ped

iatri

c Pa

tient

s, a

nd A

cute

Otit

is M

edia

in C

hild

ren:

Adul

ts: T

he u

sual

adu

lt do

sage

in th

e tre

atm

ent o

f urin

ary

tract

infe

ctio

ns is

four

teas

poon

fuls

(20

mL)

sul

fam

etho

xazo

le

and

trim

etho

prim

ora

l sus

pens

ion

ever

y 12

hou

rs fo

r 10

to 1

4 da

ys. A

n id

entic

al d

aily

dos

age

is u

sed

for 5

day

s in

the

treat

men

t of s

hige

llosi

s.Ch

ildre

n: T

he re

com

men

ded

dose

for c

hild

ren

with

urin

ary

tract

infe

ctio

ns o

r acu

te o

titis

med

ia is

40

mg/

kg

sulfa

met

hoxa

zole

and

8 m

g/kg

trim

etho

prim

per

24

hour

s, g

iven

in tw

o di

vide

d do

ses

ever

y 12

hou

rs fo

r 10

days

. An

iden

tical

dai

ly d

osag

e is

use

d fo

r 5 d

ays

in th

e tre

atm

ent o

f shi

gello

sis.

The

follo

win

g ta

ble

is a

gui

delin

e fo

r the

atta

inm

ent

of th

is d

osag

e:

Acut

e Ex

acer

batio

ns o

f Chr

onic

Bro

nchi

tis in

Adu

lts:

The

usua

l adu

lt do

sage

in th

e tre

atm

ent o

f acu

te e

xace

rbat

ions

of c

hron

ic b

ronc

hitis

is fo

ur te

aspo

onfu

ls (2

0 m

L)

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

ever

y 12

hou

rs fo

r 14

days

.Pn

eum

ocys

tis C

arin

ii Pn

eum

onia

:Tr

eatm

ent:

Adul

ts a

nd C

hild

ren:

The

reco

mm

ende

d do

sage

for t

reat

men

t of p

atie

nts

with

doc

umen

ted

Pneu

moc

ystis

ca

rinii

pneu

mon

ia is

75

to 1

00 m

g/kg

sul

fam

etho

xazo

le a

nd 1

5 to

20

mg/

kg tr

imet

hopr

im p

er 2

4 ho

urs

give

n in

equ

ally

di

vide

d do

ses

ever

y 6

hour

s fo

r 14

to 2

1 da

ys.1

0 T

he fo

llow

ing

tabl

e is

a g

uide

line

for t

he u

pper

lim

it of

this

dos

age:

For t

he lo

wer

lim

it do

se (7

5 m

g/kg

sul

fam

etho

xazo

le a

nd 1

5 m

g/kg

trim

etho

prim

per

24

hour

s) a

dmin

iste

r 75%

of t

he

dose

in th

e ab

ove

tabl

e.Pr

ophy

laxi

s:Ad

ults

: The

reco

mm

ende

d do

sage

for p

roph

ylax

is in

adu

lts is

four

teas

poon

fuls

(20

mL)

of t

he o

ral s

uspe

nsio

n da

ily.1

1Ch

ildre

n: F

or c

hild

ren,

the

reco

mm

ende

d do

se is

750

mg/

m2 /

day

sulfa

met

hoxa

zole

with

150

mg/

m2 /

day

trim

etho

prim

gi

ven

oral

ly in

equ

ally

div

ided

dos

es tw

ice

a da

y, o

n 3

cons

ecut

ive

days

per

wee

k. T

he to

tal d

aily

dos

e sh

ould

not

exc

eed

1600

mg

sulfa

met

hoxa

zole

and

320

mg

trim

etho

prim

.12

The

follo

win

g ta

ble

is a

gui

delin

e fo

r the

atta

inm

ent o

f thi

s do

sage

in c

hild

ren:

Trav

eler

's D

iarr

hea

in A

dults

: Fo

r the

trea

tmen

t of t

rave

ler's

dia

rrhe

a, th

e us

ual a

dult

dosa

ge is

four

teas

poon

fuls

(20

mL)

of s

ulfa

met

hoxa

zole

and

tri

met

hopr

im o

ral s

uspe

nsio

n ev

ery

12 h

ours

for 5

day

s.

HOW

SUP

PLIE

DSu

lfam

etho

xazo

le a

nd T

rimet

hopr

im O

ral S

uspe

nsio

n, U

SP is

sup

plie

d in

a p

urpl

e gr

ape-

flavo

red

susp

ensi

on a

nd in

a p

ink

cher

ry-fl

avor

ed s

uspe

nsio

n co

ntai

ning

200

mg

sulfa

met

hoxa

zole

and

40

mg

trim

etho

prim

per

5 m

L (te

aspo

onfu

l) bo

th

pack

aged

in 1

pin

t (47

3 m

L) b

ottle

s.St

ore

at 2

0°-2

5°C

(68°

-77°

F) [s

ee U

SP C

ontro

lled

Room

Tem

pera

ture

]. Pr

otec

t fro

m li

ght.

SHAK

E W

ELL

BEFO

RE U

SING

.Di

spen

se in

a ti

ght,

light

-res

ista

nt c

onta

iner

as

defin

ed in

the

USP,

with

a c

hild

-res

ista

nt c

losu

re (a

s re

quire

d).

To re

port

SUSP

ECTE

D AD

VERS

E RE

ACTI

ONS,

con

tact

Hi-T

ech

Phar

mac

al, C

o., I

nc. a

t 1-8

00-2

62-9

010

or F

DA a

t 1-

800-

FDA-

1088

or w

ww

.fda.

gov/

med

wat

ch.

Rx o

nly

REFE

RENC

ES1.

Kr

emer

s P,

Duv

ivie

r J, H

eusg

hem

C. P

harm

acok

inet

ic S

tudi

es o

f Co-

Trim

oxaz

ole

in M

an a

fter S

ingl

e an

d Re

peat

edDo

ses.

J C

lin P

harm

acol

. Feb

-Mar

197

4; 1

4:11

2–11

7.

2.

Kapl

an S

A, e

t al.

Phar

mac

okin

etic

Pro

file

of T

rimet

hopr

im-S

ulfa

met

hoxa

zole

in M

an. J

Infe

ct D

is. N

ov 1

973;

128

(Sup

pl):

S547

–S55

5.

3.

Varo

quau

x O,

et a

l. Ph

arm

acok

inet

ics

of th

e tri

met

hopr

im-s

ulfa

met

hoxa

zole

com

bina

tion

in th

e el

derly

.Br

J C

lin P

harm

acol

. 198

5;20

:575

–581

. 4.

Ru

doy

RC, N

elso

n JD

, Hal

talin

KC.

Ant

imic

robi

al A

gent

s Ch

emot

her.

May

197

4;5:

439–

443.

5.

Na

tiona

l Com

mitt

ee fo

r Clin

ical

Lab

orat

ory

Stan

dard

s. M

etho

ds fo

r Dilu

tion

Antim

icro

bial

Sus

cept

ibili

ty T

ests

for

Bact

eria

that

Gro

w A

erob

ical

ly; A

ppro

ved

Stan

dard

– F

ourth

Edi

tion.

NCC

LS D

ocum

ent M

7–A4

, Vol

.17,

No.

2, N

CCLS

, W

ayne

, PA,

Jan

uary

, 199

7.

6.

Hard

y DW

, et a

l. A

cont

rolle

d tri

al o

f trim

etho

prim

-sul

fam

etho

xazo

le o

r aer

osol

ized

pent

amid

ine

for s

econ

dary

prop

hyla

xis

of P

neum

ocys

tis c

arin

ii pn

eum

onia

in p

atie

nts

with

the

acqu

ired

imm

unod

efic

ienc

y sy

ndro

me.

N En

gl J

Med

. 199

2; 3

27: 1

842–

1848

. 7.

M

arin

ella

Mar

k A.

199

9. T

rimet

hopr

im-in

duce

d hy

perk

alem

ia: A

n an

alys

is o

f rep

orte

d ca

ses.

Ger

onto

l. 45

:209

–212

. 8.

M

arga

sser

y, S

. and

B. B

asta

ni. 2

002.

Life

thre

aten

ing

hype

rkal

emia

and

aci

dosi

s se

cond

ary

totri

met

hopr

im-s

ulfa

met

hoxa

zole

trea

tmen

t. J.

Nep

hrol

. 14:

410–

414.

9.

Br

umfit

t W, P

urse

ll R.

Trim

etho

prim

/Sul

fam

etho

xazo

le in

the

Trea

tmen

t of B

acte

riuria

in W

omen

. J In

fect

Dis

.No

v 19

73; 1

28 (S

uppl

):S65

7–S6

63.

10. M

asur

H. P

reve

ntio

n an

d tre

atm

ent o

f Pne

umoc

ystis

pne

umon

ia. N

Eng

l J M

ed. 1

992;

327

: 185

3–18

80.

11. R

ecom

men

datio

ns fo

r pro

phyl

axis

aga

inst

Pne

umoc

ystis

car

inii

pneu

mon

ia fo

r adu

lts a

nd a

dole

scen

ts in

fect

ed w

ithhu

man

imm

unod

efic

ienc

y vi

rus.

MM

WR.

199

2; 4

1(RR

-4):1

–11.

12

. CDC

Gui

delin

es fo

r pro

phyl

axis

aga

inst

Pne

umoc

ystis

car

inii

pneu

mon

ia fo

r chi

ldre

n in

fect

ed w

ith h

uman

imm

unod

efic

ienc

y vi

rus.

MM

WR.

199

1; 4

0(RR

-2):1

–13.

M

anuf

actu

red

by:

Hi-T

ech

Phar

mac

al C

o., I

nc.

Rev.

824:

07 7

/11

Amity

ville

, New

Yor

k 11

701

Child

ren

2 m

onth

s of

age

or o

lder

:

Dose

— e

very

12

hour

s

Dose

— e

very

6 h

ours

Dose

— e

very

12

hour

s






Back

Page #8 Page #9 Page #10Page #3 Page #4 Page #5 Page #6 Page #7Page #2(Back of Cover)

Page #11 Page #12 Page #13 Page #14 Page #15


APPROVAL SIGNATURE

APPROVED

REVISE AND RE-PROOF


GRAPHICS PROOFSize:

Rev:


Co

py

#4

#4BLACK

24.625"

2.000" 1.813" 1.750" 1.688" 1.688" 1.750" 1.750" 1.750" 1.750" 1.688" 1.688" 1.750" 1.813" 1.750"

4.12

5"

CH

3

HN 2

SO

NH

2

NO

N

N

NH

2

CH

2N

H2

CH

O3

OC

H3

OC

H3

SULF

AMET

HOXA

ZOLE

AND

TRI

MET

HOPR

IMOR

AL S

USPE

NSIO

N, U

SPTo

redu

ce th

e de

velo

pmen

t of d

rug-

resi

stan

t bac

teria

and

mai

ntai

n th

e ef

fect

iven

ess

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

or

al s

uspe

nsio

n an

d ot

her a

ntib

acte

rial d

rugs

, sul

fam

etho

xazo

le a

nd tr

imet

hopr

im o

ral s

uspe

nsio

n sh

ould

be

used

onl

y to

tre

at o

r pre

vent

infe

ctio

ns th

at a

re p

rove

n or

stro

ngly

sus

pect

ed to

be

caus

ed b

y ba

cter

ia.

DESC

RIPT

ION

Sulfa

met

hoxa

zole

and

trim

etho

prim

is a

syn

thet

ic a

ntib

acte

rial c

ombi

natio

n pr

oduc

t con

tain

ing

200

mg

sulfa

met

hoxa

zole

an

d 40

mg

trim

etho

prim

per

5 m

L fo

r ora

l adm

inis

tratio

n.

Sulfa

met

hoxa

zole

is N

1 -(5

-met

hyl-3

-isox

azol

yl)s

ulfa

nila

mid

e; th

e m

olec

ular

form

ula

is C

10H 1

1N3O

3S. I

t is

an a

lmos

t whi

te,

odor

less

, tas

tele

ss c

ompo

und

with

a m

olec

ular

wei

ght o

f 253

.28

and

the

follo

win

g st

ruct

ural

form

ula:

Trim

etho

prim

is 2

,4-d

iam

ino-

5-(3

,4,5

-trim

etho

xybe

nzyl

)pyr

imid

ine;

the

mol

ecul

ar fo

rmul

a is

C14

H 18N

4O3.

It is

a w

hite

to

light

yel

low

, odo

rless

, bitt

er c

ompo

und

with

a m

olec

ular

wei

ght o

f 290

.3 a

nd th

e fo

llow

ing

stru

ctur

al fo

rmul

a:

Inac

tive

ingr

edie

nts:

alc

ohol

0.2

6%, m

ethy

lpar

aben

0.1

% a

nd s

odiu

m b

enzo

ate

0.1%

(add

ed a

s pr

eser

vativ

es),

carb

oxym

ethy

lcel

lulo

se s

odiu

m, c

itric

aci

d (a

nhyd

rous

), gl

ycer

in, m

icro

crys

talli

ne c

ellu

lose

, pol

ysor

bate

80,

pur

ified

wat

er,

sacc

harin

sod

ium

, and

sor

bito

l. Th

e lig

ht p

urpl

e, g

rape

flav

ored

sus

pens

ion

cont

ains

the

follo

win

g ad

ditio

nal i

nact

ive

ingr

edie

nts:

FD&

C Re

d No

. 40,

FD&

C Bl

ue N

o. 1

and

nat

ural

and

arti

ficia

l gra

pe fl

avor

. The

pin

k, c

herr

y fla

vore

d su

spen

sion

co

ntai

ns th

e fo

llow

ing

addi

tiona

l ina

ctiv

e in

gred

ient

s: F

D&C

Red

No. 4

0, F

D&C

Yello

w N

o. 6

and

arti

ficia

l che

rry

flavo

r.CL

INIC

AL P

HARM

ACOL

OGY

Sulfa

met

hoxa

zole

and

trim

etho

prim

is ra

pidl

y ab

sorb

ed fo

llow

ing

oral

adm

inis

tratio

n. B

oth

sulfa

met

hoxa

zole

and

tri

met

hopr

im e

xist

in th

e bl

ood

as u

nbou

nd, p

rote

in-b

ound

and

met

abol

ized

form

s; s

ulfa

met

hoxa

zole

als

o ex

ists

as

the

conj

ugat

ed fo

rm. T

he m

etab

olis

m o

f sul

fam

etho

xazo

le o

ccur

s pr

edom

inat

ely

by N

4-ac

etyl

atio

n, a

lthou

gh th

e gl

ucur

onid

e co

njug

ate

has

been

iden

tifie

d. T

he p

rinci

pal m

etab

olite

s of

trim

etho

prim

are

the

1- a

nd 3

-oxi

des

and

the

3’- a

nd 4

’-hyd

roxy

de

rivat

ives

. The

free

form

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re c

onsi

dere

d to

be

the

ther

apeu

tical

ly a

ctiv

e fo

rms.

Ap

prox

imat

ely

70%

of s

ulfa

met

hoxa

zole

and

44%

of t

rimet

hopr

im a

re b

ound

to p

lasm

a pr

otei

ns. T

he p

rese

nce

of 1

0 m

g pe

rcen

t sul

fam

etho

xazo

le in

pla

sma

decr

ease

s th

e pr

otei

n bi

ndin

g of

trim

etho

prim

by

an in

sign

ifica

nt d

egre

e; tr

imet

hopr

im

does

not

influ

ence

the

prot

ein

bind

ing

of s

ulfa

met

hoxa

zole

.Pe

ak b

lood

leve

ls fo

r the

indi

vidu

al c

ompo

nent

s oc

cur 1

to 4

hou

rs a

fter o

ral a

dmin

istra

tion.

The

mea

n se

rum

hal

f-liv

es o

f su

lfam

etho

xazo

le a

nd tr

imet

hopr

im a

re 1

0 an

d 8

to 1

0 ho

urs,

resp

ectiv

ely.

How

ever

, pat

ient

s w

ith s

ever

ely

impa

ired

rena

l fu

nctio

n ex

hibi

t an

incr

ease

in th

e ha

lf-liv

es o

f bot

h co

mpo

nent

s, re

quiri

ng d

osag

e re

gim

en a

djus

tmen

t (se

e DO

SAGE

AND

AD

MIN

ISTR

ATIO

N se

ctio

n). D

etec

tabl

e am

ount

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re p

rese

nt in

the

bloo

d 24

hou

rs

afte

r dru

g ad

min

istra

tion.

Dur

ing

adm

inis

tratio

n of

800

mg

sulfa

met

hoxa

zole

and

160

mg

trim

etho

prim

b.i.

d., t

he m

ean

stea

dy-s

tate

pla

sma

conc

entra

tion

of tr

imet

hopr

im w

as 1

.72

μg/

mL.

The

ste

ady-

stat

e m

ean

plas

ma

leve

ls o

f fre

e an

d to

tal

sulfa

met

hoxa

zole

wer

e 57

.4 μ

g/m

L an

d 68

.0 μ

g/m

L, re

spec

tivel

y. T

hese

ste

ady-

stat

e le

vels

wer

e ac

hiev

ed a

fter t

hree

day

s of

dru

g ad

min

istra

tion.

1 Ex

cret

ion

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

is p

rimar

ily b

y th

e ki

dney

s th

roug

h bo

th

glom

erul

ar fi

ltrat

ion

and

tubu

lar s

ecre

tion.

Urin

e co

ncen

tratio

ns o

f bot

h su

lfam

etho

xazo

le a

nd tr

imet

hopr

im a

re

cons

ider

ably

hig

her t

han

are

the

conc

entra

tions

in th

e bl

ood.

The

ave

rage

per

cent

age

of th

e do

se re

cove

red

in u

rine

from

0

to 7

2 ho

urs

afte

r a s

ingl

e or

al d

ose

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

is 8

4.5%

for t

otal

sul

fona

mid

e an

d 66

.8%

for

free

trim

etho

prim

. Thi

rty p

erce

nt o

f the

tota

l sul

fona

mid

e is

exc

rete

d as

free

sul

fam

etho

xazo

le, w

ith th

e re

mai

ning

as

N 4-a

cety

late

d m

etab

olite

.2 W

hen

adm

inis

tere

d to

geth

er a

s su

lfam

etho

xazo

le a

nd tr

imet

hopr

im, n

eith

er s

ulfa

met

hoxa

zole

no

r trim

etho

prim

affe

cts

the

urin

ary

excr

etio

n pa

ttern

of t

he o

ther

.Bo

th s

ulfa

met

hoxa

zole

and

trim

etho

prim

dis

tribu

te to

spu

tum

, vag

inal

flui

d an

d m

iddl

e ea

r flu

id; t

rimet

hopr

im a

lso

dist

ribut

es to

bro

nchi

al s

ecre

tions

, and

bot

h pa

ss th

e pl

acen

tal b

arrie

r and

are

exc

rete

d in

hum

an m

ilk.

Geria

tric

Phar

mac

okin

etic

sTh

e ph

arm

acok

inet

ics

of s

ulfa

met

hoxa

zole

800

mg

and

trim

etho

prim

160

mg

wer

e st

udie

d in

6 g

eria

tric

subj

ects

(mea

n ag

e: 7

8.6

year

s) a

nd 6

you

ng h

ealth

y su

bjec

ts (m

ean

age:

29.

3 ye

ars)

usi

ng a

non

-U.S

. app

rove

d fo

rmul

atio

n.

Phar

mac

okin

etic

val

ues

for s

ulfa

met

hoxa

zole

in g

eria

tric

subj

ects

wer

e si

mila

r to

thos

e ob

serv

ed in

you

ng a

dult

subj

ects

. Th

e m

ean

rena

l cle

aran

ce o

f trim

etho

prim

was

sig

nific

antly

low

er in

ger

iatri

c su

bjec

ts c

ompa

red

with

you

ng a

dult

subj

ects

(1

9 m

L/h/

kg v

s. 5

5 m

L/h/

kg).

How

ever

, afte

r nor

mal

izing

by

body

wei

ght,

the

appa

rent

tota

l bod

y cl

eara

nce

of

trim

etho

prim

was

on

aver

age

19%

low

er in

ger

iatri

c su

bjec

ts c

ompa

red

with

you

ng a

dult

subj

ects

.3M

icro

biol

ogy

Sulfa

met

hoxa

zole

inhi

bits

bac

teria

l syn

thes

is o

f dih

ydro

folic

aci

d by

com

petin

g w

ith p

ara-

amin

oben

zoic

aci

d (P

ABA)

. Tr

imet

hopr

im b

lock

s th

e pr

oduc

tion

of te

trahy

drof

olic

aci

d fro

m d

ihyd

rofo

lic a

cid

by b

indi

ng to

and

reve

rsib

ly in

hibi

ting

the

requ

ired

enzy

me,

dih

ydro

fola

te re

duct

ase.

Thu

s, s

ulfa

met

hoxa

zole

and

trim

etho

prim

blo

cks

two

cons

ecut

ive

step

s in

th

e bi

osyn

thes

is o

f nuc

leic

aci

ds a

nd p

rote

ins

esse

ntia

l to

man

y ba

cter

ia.

In v

itro

stud

ies

have

sho

wn

that

bac

teria

l res

ista

nce

deve

lops

mor

e sl

owly

with

bot

h su

lfam

etho

xazo

le a

nd tr

imet

hopr

im in

co

mbi

natio

n th

an w

ith e

ither

sul

fam

etho

xazo

le o

r trim

etho

prim

alo

ne.

Sulfa

met

hoxa

zole

and

trim

etho

prim

hav

e be

en s

how

n to

be

activ

e ag

ains

t mos

t stra

ins

of th

e fo

llow

ing

mic

roor

gani

sms,

bo

th in

vitr

o an

d in

clin

ical

infe

ctio

ns a

s de

scrib

ed in

the

INDI

CATI

ONS

AND

USAG

E se

ctio

n.Ae

robi

c gr

am-p

ositi

ve m

icro

orga

nism

s:

Stre

ptoc

occu

s pn

eum

onia

e Ae

robi

c gr

am-n

egat

ive

mic

roor

gani

sms:

Es

cher

ichi

a co

li (in

clud

ing

susc

eptib

le e

nter

otox

igen

ic s

train

s im

plic

ated

in tr

avel

er's

dia

rrhe

a)Kl

ebsi

ella

spe

cies

Ente

roba

cter

spe

cies

Haem

ophi

lus

influ

enza

eM

orga

nella

mor

gani

iPr

oteu

s m

irabi

lisPr

oteu

s vu

lgar

isSh

igel

la fl

exne

riSh

igel

la s

onne

iOt

her O

rgan

ism

s:

Pneu

moc

ystis

car

inii

Susc

eptib

ility

Tes

ting

Met

hods

: Di

lutio

n Te

chni

ques

: Qu

antit

ativ

e m

etho

ds a

re u

sed

to d

eter

min

e an

timic

robi

al m

inim

um in

hibi

tory

con

cent

ratio

ns (M

ICs)

. The

se M

ICs

prov

ide

estim

ates

of t

he s

usce

ptib

ility

of b

acte

ria to

ant

imic

robi

al c

ompo

unds

. The

MIC

s sh

ould

be

dete

rmin

ed u

sing

a

stan

dard

ized

proc

edur

e. S

tand

ardi

zed

proc

edur

es a

re b

ased

on

a di

lutio

n m

etho

d4 (b

roth

or a

gar)

or e

quiv

alen

t with

st

anda

rdize

d in

ocul

um c

once

ntra

tions

and

sta

ndar

dize

d co

ncen

tratio

ns o

f sul

fam

etho

xazo

le/tr

imet

hopr

im p

owde

r. Th

e M

IC v

alue

s sh

ould

be

inte

rpre

ted

acco

rdin

g to

the

follo

win

g cr

iteria

: Fo

r tes

ting

Ente

roba

cter

iace

ae:

MIC

(μg/

mL)

In

terp

reta

tion

≤ 2/

38

Susc

eptib

le (S

)≥

4/76

Re

sist

ant (

R)W

hen

test

ing

eith

er H

aem

ophi

lus

influ

enza

ea o

r Stre

ptoc

occu

s pn

eum

onia

eb:

MIC

(μg/

mL)

In

terp

reta

tionb

≤ 0.

5/9.

5 Su

scep

tible

(S)

1/19

– 2

/38

Inte

rmed

iate

(I)

≥ 4/

76

Resi

stan

t (R)

a.Th

ese

inte

rpre

tativ

e st

anda

rds

are

appl

icab

le o

nly

to b

roth

mic

rodi

lutio

n su

scep

tibili

ty te

sts

with

Hae

mop

hilu

s in

fluen

zae

usin

g Ha

emop

hilu

s Te

st M

ediu

m (H

TM).4

b.

Thes

e in

terp

reta

tive

stan

dard

s ar

e ap

plic

able

onl

y to

bro

th m

icro

dilu

tion

susc

eptib

ility

test

s us

ing

catio

n-ad

just

edM

uelle

r-Hi

nton

bro

th w

ith 2

% to

5%

lyse

d ho

rse

bloo

d.4

A re

port

of "S

usce

ptib

le" i

ndic

ates

that

the

path

ogen

is li

kely

to b

e in

hibi

ted

if th

e an

timic

robi

al c

ompo

und

in th

e bl

ood

reac

hes

the

conc

entra

tions

usu

ally

ach

ieva

ble.

A re

port

of "I

nter

med

iate

" ind

icat

es th

at th

e re

sult

shou

ld b

e co

nsid

ered

eq

uivo

cal,

and,

if th

e m

icro

orga

nism

is n

ot fu

lly s

usce

ptib

le to

alte

rnat

ive,

clin

ical

ly fe

asib

le d

rugs

, the

test

sho

uld

be

repe

ated

. Thi

s ca

tego

ry im

plie

s po

ssib

le c

linic

al a

pplic

abili

ty in

bod

y si

tes

whe

re th

e dr

ug is

phy

siol

ogic

ally

con

cent

rate

d or

in s

ituat

ions

whe

re h

igh

dosa

ge o

f dru

g ca

n be

use

d. T

his

cate

gory

als

o pr

ovid

es a

buf

fer z

one

whi

ch p

reve

nts

smal

l un

cont

rolle

d te

chni

cal f

acto

rs fr

om c

ausi

ng m

ajor

dis

crep

anci

es in

inte

rpre

tatio

n. A

repo

rt of

"Res

ista

nt" i

ndic

ates

that

the

path

ogen

is n

ot li

kely

to b

e in

hibi

ted

if th

e an

timic

robi

al c

ompo

und

in th

e bl

ood

reac

hes

the

conc

entra

tions

usu

ally

ac

hiev

able

; oth

er th

erap

y sh

ould

be

sele

cted

. Qu

ality

Con

trol:

Stan

dard

ized

susc

eptib

ility

test

pro

cedu

res

requ

ire th

e us

e of

labo

rato

ry c

ontro

l mic

roor

gani

sms

to c

ontro

l the

tech

nica

l as

pect

s of

the

labo

rato

ry p

roce

dure

s. S

tand

ard

sulfa

met

hoxa

zole

/trim

etho

prim

pow

der s

houl

d pr

ovid

e th

e fo

llow

ing

rang

e of

val

ues:

M

icro

orga

nism

MIC

(μg/

mL)

Esch

eric

hia

coli

ATCC

259

22

≤ 0.

5/9.

5Ha

emop

hilu

s in

fluen

zaec

AT

CC 4

9247

0.

03/0

.59

– 0.

25/4

.75

Stre

ptoc

occu

s pn

eum

onia

ed

ATCC

496

19

0.12

/2.4

– 1

/19

c.Th

is q

ualit

y co

ntro

l ran

ge is

app

licab

le o

nly

to H

aem

ophi

lus

influ

enza

e AT

CC 4

9247

test

ed b

y br

oth

mic

rodi

lutio

npr

oced

ure

usin

g Ha

emop

hilu

s Te

st M

ediu

m (H

TM).4

d.Th

is q

ualit

y co

ntro

l ran

ge is

app

licab

le to

test

s pe

rform

ed b

y th

e br

oth

mic

rodi

lutio

n m

etho

d on

ly u

sing

cat

ion-

adju

sted

Mue

ller-

Hint

on b

roth

with

2%

to 5

% ly

sed

hors

e bl

ood.

4 Di

ffusi

on T

echn

ique

s:

Quan

titat

ive

met

hods

that

requ

ire m

easu

rem

ent o

f zon

e di

amet

ers

also

pro

vide

repr

oduc

ible

est

imat

es o

f the

sus

cept

ibili

ty

of b

acte

ria to

ant

imic

robi

al c

ompo

unds

. One

suc

h st

anda

rdize

d pr

oced

ure5

requ

ires

the

use

of s

tand

ardi

zed

inoc

ulum

co

ncen

tratio

ns. T

his

proc

edur

e us

es p

aper

dis

ks im

preg

nate

d w

ith 1

.25/

23.7

5 μ

g of

sul

fam

etho

xazo

le/tr

imet

hopr

im to

test

th

e su

scep

tibili

ty o

f mic

roor

gani

sms

to s

ulfa

met

hoxa

zole

/trim

etho

prim

. Re

ports

from

the

labo

rato

ry p

rovi

ding

resu

lts o

f the

sta

ndar

d si

ngle

-dis

k su

scep

tibili

ty te

st w

ith a

1.2

5/23

.75

μg

of

sulfa

met

hoxa

zole

/trim

etho

prim

dis

k sh

ould

be

inte

rpre

ted

acco

rdin

g to

the

follo

win

g cr

iteria

: Fo

r tes

ting

eith

er E

nter

obac

teria

ceae

or H

aem

ophi

lus

influ

enza

ee:

Zone

Dia

met

er (m

m)

Inte

rpre

tatio

n≥

16

Susc

eptib

le (S

)11

– 1

5 In

term

edia

te (I

)≤

10

Resi

stan

t (R)

e.Th

ese

zone

dia

met

er s

tand

ards

are

app

licab

le o

nly

for d

isk

diffu

sion

test

ing

with

Hae

mop

hilu

s in

fluen

zae

and

Haem

ophi

lus

Test

Med

ium

(HTM

).5

Whe

n te

stin

g St

rept

ococ

cus

pneu

mon

iaef

:Zo

ne D

iam

eter

(mm

) In

terp

reta

tion

≥ 19

Su

scep

tible

(S)

16 –

18

Inte

rmed

iate

(I)

≤ 15

Re

sist

ant (

R)f.

Thes

e zo

ne d

iam

eter

inte

rpre

tativ

e st

anda

rds

are

appl

icab

le o

nly

to te

sts

perfo

rmed

usi

ng M

uelle

r-Hi

nton

aga

rsu

pple

men

ted

with

5%

def

ibrin

ated

she

ep b

lood

whe

n in

cuba

ted

in 5

% C

O 2.5

In

terp

reta

tion

shou

ld b

e as

sta

ted

abov

e fo

r res

ults

usi

ng d

ilutio

n te

chni

ques

. Int

erpr

etat

ion

invo

lves

cor

rela

tion

of th

e di

amet

er o

btai

ned

in th

e di

sk te

st w

ith th

e M

IC fo

r sul

fam

etho

xazo

le/tr

imet

hopr

im.

Qual

ity C

ontro

l: As

with

sta

ndar

dize

d di

lutio

n te

chni

ques

, diff

usio

n m

etho

ds re

quire

the

use

of la

bora

tory

con

trol m

icro

orga

nism

s th

at a

re

used

to c

ontro

l the

tech

nica

l asp

ects

of t

he la

bora

tory

pro

cedu

res.

For

the

diffu

sion

tech

niqu

e, th

e 1.

25/2

3.75

μg

sulfa

met

hoxa

zole

/trim

etho

prim

dis

k* s

houl

d pr

ovid

e th

e fo

llow

ing

zone

dia

met

ers

in th

ese

labo

rato

ry te

st q

ualit

y co

ntro

l st

rain

s:M

icro

orga

nism

Zone

Dia

met

er R

ange

s (m

m)

Esch

eric

hia

coli

AT

CC 2

5922

23

–29

Haem

ophi

lus

influ

enza

eg

ATCC

492

47

24–3

2 St

rept

ococ

cus

pneu

mon

iaeh

AT

CC 4

9619

20

–28

* M

uelle

r-Hi

nton

aga

r sho

uld

be c

heck

ed fo

r exc

essi

ve le

vels

of t

hym

idin

e or

thym

ine.

To

dete

rmin

e w

heth

erM

uelle

r-Hi

nton

med

ium

has

suf

ficie

ntly

low

leve

ls o

f thy

mid

ine

and

thym

ine,

an

Ente

roco

ccus

faec

alis

(ATC

C 29

212

or

ATCC

331

86) m

ay b

e te

sted

with

sul

fam

etho

xazo

le/tr

imet

hopr

im d

isks

. A zo

ne o

f inh

ibiti

on ≥

20 m

m th

at is

ess

entia

lly

free

of fi

ne c

olon

ies

indi

cate

s a

suffi

cien

tly lo

w le

vel o

f thy

mid

ine

and

thym

ine.

g.

This

qua

lity

cont

rol r

ange

is a

pplic

able

onl

y to

Hae

mop

hilu

s in

fluen

zae

ATCC

492

47 te

sted

by

a di

sk d

iffus

ion

proc

edur

eus

ing

Haem

ophi

lus

Test

Med

ium

(HTM

).5h.

This

qua

lity

cont

rol r

ange

is a

pplic

able

onl

y to

test

s pe

rform

ed b

y di

sk d

iffus

ion

usin

g M

uelle

r-Hi

nton

aga

r sup

plem

ente

dw

ith 5

% d

efib

rinat

ed s

heep

blo

od w

hen

incu

bate

d in

5%

CO 2

.5IN

DICA

TION

S AN

D US

AGE

To re

duce

the

deve

lopm

ent o

f dru

g-re

sist

ant b

acte

ria a

nd m

aint

ain

the

effe

ctiv

enes

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im

oral

sus

pens

ion

and

othe

r ant

ibac

teria

l dru

gs, s

ulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

shou

ld b

e us

ed o

nly

to

treat

or p

reve

nt in

fect

ions

that

are

pro

ven

or s

trong

ly s

uspe

cted

to b

e ca

used

by

susc

eptib

le b

acte

ria. W

hen

cultu

re a

nd

susc

eptib

ility

info

rmat

ion

are

avai

labl

e, th

ey s

houl

d be

con

side

red

in s

elec

ting

or m

odify

ing

antib

acte

rial t

hera

py. I

n th

e ab

senc

e of

suc

h da

ta, l

ocal

epi

dem

iolo

gy a

nd s

usce

ptib

ility

pat

tern

s m

ay c

ontri

bute

to e

mpi

ric s

elec

tion

of th

erap

y.Ur

inar

y Tr

act I

nfec

tions

: For

the

treat

men

t of u

rinar

y tra

ct in

fect

ions

due

to s

usce

ptib

le s

train

s of

the

follo

win

g or

gani

sms:

Es

cher

ichi

a co

li, K

lebs

iella

spe

cies

, Ent

erob

acte

r spe

cies

, Mor

gane

lla m

orga

nii,

Prot

eus

mira

bilis

and

Pro

teus

vul

garis

. It i

s re

com

men

ded

that

initi

al e

piso

des

of u

ncom

plic

ated

urin

ary

tract

infe

ctio

ns b

e tre

ated

with

a s

ingl

e ef

fect

ive

antib

acte

rial

agen

t rat

her t

han

the

com

bina

tion.

Acut

e Ot

itis

Med

ia: F

or th

e tre

atm

ent o

f acu

te o

titis

med

ia in

ped

iatri

c pa

tient

s du

e to

sus

cept

ible

stra

ins

of S

trept

ococ

cus

pneu

mon

iae

or H

aem

ophi

lus

influ

enza

e w

hen

in th

e ju

dgm

ent o

f the

phy

sici

an s

ulfa

met

hoxa

zole

and

trim

etho

prim

offe

rs

som

e ad

vant

age

over

the

use

of o

ther

ant

imic

robi

al a

gent

s. T

o da

te, t

here

are

lim

ited

data

on

the

safe

ty o

f rep

eate

d us

e of

su

lfam

etho

xazo

le a

nd tr

imet

hopr

im in

ped

iatri

c pa

tient

s un

der t

wo

year

s of

age

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

not

in

dica

ted

for p

roph

ylac

tic o

r pro

long

ed a

dmin

istra

tion

in o

titis

med

ia a

t any

age

.Ac

ute

Exac

erba

tions

of C

hron

ic B

ronc

hitis

in A

dults

: For

the

treat

men

t of a

cute

exa

cerb

atio

ns o

f chr

onic

bro

nchi

tis d

ue to

su

scep

tible

stra

ins

of S

trept

ococ

cus

pneu

mon

iae

or H

aem

ophi

lus

influ

enza

e w

hen

in th

e ju

dgm

ent o

f the

phy

sici

an

sulfa

met

hoxa

zole

and

trim

etho

prim

offe

rs s

ome

adva

ntag

e ov

er th

e us

e of

a s

ingl

e an

timic

robi

al a

gent

.Sh

igel

losi

s: F

or th

e tre

atm

ent o

f ent

eriti

s ca

used

by

susc

eptib

le s

train

s of

Shi

gella

flex

neri

and

Shig

ella

son

nei w

hen

antib

acte

rial t

hera

py is

indi

cate

d.Pn

eum

ocys

tis C

arin

ii Pn

eum

onia

: For

the

treat

men

t of d

ocum

ente

d Pn

eum

ocys

tis c

arin

ii pn

eum

onia

and

for p

roph

ylax

is

agai

nst P

neum

ocys

tis c

arin

ii pn

eum

onia

in in

divi

dual

s w

ho a

re im

mun

osup

pres

sed

and

cons

ider

ed to

be

at a

n in

crea

sed

risk

of d

evel

opin

g Pn

eum

ocys

tis c

arin

ii pn

eum

onia

.Tr

avel

ers’

Dia

rrhe

a In

Adu

lts: F

or th

e tre

atm

ent o

f tra

vele

rs’ d

iarr

hea

due

to s

usce

ptib

le s

train

s of

ent

erot

oxig

enic

E. c

oli.

CONT

RAIN

DICA

TION

SSu

lfam

etho

xazo

le a

nd tr

imet

hopr

im is

con

train

dica

ted

in p

atie

nts

with

a k

now

n hy

pers

ensi

tivity

to tr

imet

hopr

im o

r su

lfona

mid

es, i

n pa

tient

s w

ith a

his

tory

of d

rug-

indu

ced

imm

une

thro

mbo

cyto

peni

a w

ith u

se o

f trim

etho

prim

and

/or

sulfo

nam

ides

, and

in p

atie

nts

with

doc

umen

ted

meg

alob

last

ic a

nem

ia d

ue to

fola

te d

efic

ienc

y. S

ulfa

met

hoxa

zole

and

tri

met

hopr

im is

als

o co

ntra

indi

cate

d in

pre

gnan

t pat

ient

s an

d nu

rsin

g m

othe

rs, b

ecau

se s

ulfo

nam

ides

pas

s th

e pl

acen

ta

and

are

excr

eted

in th

e m

ilk a

nd m

ay c

ause

ker

nict

erus

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

con

train

dica

ted

in p

edia

tric

patie

nts

less

than

2 m

onth

s of

age

. Sul

fam

etho

xazo

le a

nd tr

imet

hopr

im is

als

o co

ntra

indi

cate

d in

pat

ient

s w

ith m

arke

d he

patic

dam

age

or w

ith s

ever

e re

nal i

nsuf

ficie

ncy

whe

n re

nal f

unct

ion

stat

us c

anno

t be

mon

itore

d.W

ARNI

NGS

FATA

LITI

ES A

SSOC

IATE

D W

ITH

THE

ADM

INIS

TRAT

ION

OF S

ULFO

NAM

IDES

, ALT

HOUG

H RA

RE, H

AVE

OCCU

RRED

DUE

TO

SEV

ERE

REAC

TION

S, IN

CLUD

ING

STEV

ENS-

JOHN

SON

SYND

ROM

E, T

OXIC

EPI

DERM

AL N

ECRO

LYSI

S, F

ULM

INAN

T HE

PATI

C NE

CROS

IS, A

GRAN

ULOC

YTOS

IS, A

PLAS

TIC

ANEM

IA A

ND O

THER

BLO

OD D

YSCR

ASIA

S.SU

LFON

AMID

ES, I

NCLU

DING

SUL

FONA

MID

E-CO

NTAI

NING

PRO

DUCT

S SU

CH A

S SU

LFAM

ETHO

XAZO

LE/T

RIM

ETHO

PRIM

, SH

OULD

BE

DISC

ONTI

NUED

AT

THE

FIRS

T AP

PEAR

ANCE

OF

SKIN

RAS

H OR

ANY

SIG

N OF

ADV

ERSE

REA

CTIO

N. In

rare

in

stan

ces,

a s

kin

rash

may

be

follo

wed

by

a m

ore

seve

re re

actio

n, s

uch

as S

teve

ns-J

ohns

on s

yndr

ome,

toxi

c ep

ider

mal

ne

crol

ysis

, hep

atic

nec

rosi

s, a

nd s

erio

us b

lood

dis

orde

rs (s

ee P

RECA

UTIO

NS).

Clin

ical

sig

ns, s

uch

as ra

sh, s

ore

thro

at,

feve

r, ar

thra

lgia

, pal

lor,

purp

ura

or ja

undi

ce m

ay b

e ea

rly in

dica

tions

of s

erio

us re

actio

ns.

Coug

h, s

hortn

ess

of b

reat

h, a

nd p

ulm

onar

y in

filtra

tes

are

hype

rsen

sitiv

ity re

actio

ns o

f the

resp

irato

ry tr

act t

hat h

ave

been

repo

rted

in a

ssoc

iatio

n w

ith s

ulfo

nam

ide

treat

men

t.Th

rom

bocy

tope

nia

Sulfa

met

hoxa

zole

/trim

etho

prim

-indu

ced

thro

mbo

cyto

peni

a m

ay b

e an

imm

une-

med

iate

d di

sord

er. S

ever

e ca

ses

of

thro

mbo

cyto

peni

a th

at a

re fa

tal o

r life

thre

aten

ing

have

bee

n re

porte

d. T

hrom

bocy

tope

nia

usua

lly re

solv

es w

ithin

a w

eek

upon

dis

cont

inua

tion

of s

ulfa

met

hoxa

zole

/trim

etho

prim

.Th

e su

lfona

mid

es s

houl

d no

t be

used

for t

he tr

eatm

ent o

f gro

up A

β-h

emol

ytic

stre

ptoc

occa

l inf

ectio

ns. I

n an

est

ablis

hed

infe

ctio

n, th

ey w

ill n

ot e

radi

cate

the

stre

ptoc

occu

s an

d, th

eref

ore,

will

not

pre

vent

seq

uela

e su

ch a

s rh

eum

atic

feve

r.Cl

ostri

dium

diff

icile

ass

ocia

ted

diar

rhea

(CDA

D) h

as b

een

repo

rted

with

use

of n

early

all

antib

acte

rial a

gent

s, in

clud

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

, and

may

rang

e in

sev

erity

from

mild

dia

rrhe

a to

fata

l col

itis.

Tre

atm

ent w

ith

antib

acte

rial a

gent

s al

ters

the

norm

al fl

ora

of th

e co

lon

lead

ing

to o

verg

row

th o

f C. d

iffic

ile.

C. d

iffic

ile p

rodu

ces

toxi

ns A

and

B w

hich

con

tribu

te to

the

deve

lopm

ent o

f CDA

D. H

yper

toxi

n pr

oduc

ing

stra

ins

of C

. di

ffici

le c

ause

incr

ease

d m

orbi

dity

and

mor

talit

y, a

s th

ese

infe

ctio

ns c

an b

e re

fract

ory

to a

ntim

icro

bial

ther

apy

and

may

re

quire

col

ecto

my.

CDA

D m

ust b

e co

nsid

ered

in a

ll pa

tient

s w

ho p

rese

nt w

ith d

iarr

hea

follo

win

g an

tibio

tic u

se. C

aref

ul

med

ical

his

tory

is n

eces

sary

sin

ce C

DAD

has

been

repo

rted

to o

ccur

ove

r tw

o m

onth

s af

ter t

he a

dmin

istra

tion

of

antib

acte

rial a

gent

s.If

CDAD

is s

uspe

cted

or c

onfir

med

, ong

oing

ant

ibio

tic u

se n

ot d

irect

ed a

gain

st C

. diff

icile

may

nee

d to

be

disc

ontin

ued.

Ap

prop

riate

flui

d an

d el

ectro

lyte

man

agem

ent,

prot

ein

supp

lem

enta

tion,

ant

ibio

tic tr

eatm

ent o

f C. d

iffic

ile, a

nd s

urgi

cal

eval

uatio

n sh

ould

be

inst

itute

d as

clin

ical

ly in

dica

ted.

PREC

AUTI

ONS

Gene

ral

Pres

crib

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

ora

l sus

pens

ion

in th

e ab

senc

e of

a p

rove

n or

stro

ngly

sus

pect

ed b

acte

rial

infe

ctio

n or

a p

roph

ylac

tic in

dica

tion

is u

nlik

ely

to p

rovi

de b

enef

it to

the

patie

nt a

nd in

crea

ses

the

risk

of th

e de

velo

pmen

t of

dru

g-re

sist

ant b

acte

ria.

Sulfa

met

hoxa

zole

and

trim

etho

prim

sho

uld

be g

iven

with

cau

tion

to p

atie

nts

with

impa

ired

rena

l or h

epat

ic fu

nctio

n, to

th

ose

with

pos

sibl

e fo

late

def

icie

ncy

(e.g

., th

e el

derly

, chr

onic

alc

ohol

ics,

pat

ient

s re

ceiv

ing

antic

onvu

lsan

t the

rapy

, pa

tient

s w

ith m

alab

sorp

tion

synd

rom

e, a

nd p

atie

nts

in m

alnu

tritio

n st

ates

) and

to th

ose

with

sev

ere

alle

rgie

s or

bro

nchi

al

asth

ma.

In g

luco

se-6

-pho

spha

te d

ehyd

roge

nase

def

icie

nt in

divi

dual

s, h

emol

ysis

may

occ

ur. T

his

reac

tion

is fr

eque

ntly

do

se-r

elat

ed (s

ee C

LINI

CAL

PHAR

MAC

OLOG

Y an

d DO

SAGE

AND

ADM

INIS

TRAT

ION)

.Ca

ses

of h

ypog

lyce

mia

in n

on-d

iabe

tic p

atie

nts

treat

ed w

ith s

ulfa

met

hoxa

zole

and

trim

etho

prim

are

see

n ra

rely

, usu

ally

oc

curr

ing

afte

r a fe

w d

ays

of th

erap

y. P

atie

nts

with

rena

l dys

func

tion,

live

r dis

ease

, mal

nutri

tion

or th

ose

rece

ivin

g hi

gh

dose

s of

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im a

re p

artic

ular

ly a

t ris

k.

Hem

atol

ogic

al c

hang

es in

dica

tive

of fo

lic a

cid

defic

ienc

y m

ay o

ccur

in e

lder

ly p

atie

nts

or in

pat

ient

s w

ith p

reex

istin

g fo

lic

acid

def

icie

ncy

or k

idne

y fa

ilure

. The

se e

ffect

s ar

e re

vers

ible

by

folin

ic a

cid

ther

apy.

Tr

imet

hopr

im h

as b

een

note

d to

impa

ir ph

enyl

alan

ine

met

abol

ism

, but

this

is o

f no

sign

ifica

nce

in p

heny

lket

onur

ic p

atie

nts

on a

ppro

pria

te d

ieta

ry re

stric

tion.

As

with

all

drug

s co

ntai

ning

sul

fona

mid

es, c

autio

n is

adv

isab

le in

pat

ient

s w

ith p

orph

yria

or t

hyro

id d

ysfu

nctio

n.Us

e in

the

Trea

tmen

t of a

nd P

roph

ylax

is fo

r Pne

umoc

ystis

Car

inii

Pneu

mon

ia in

Pat

ient

s w

ith A

cqui

red

Imm

unod

efic

ienc

y Sy

ndro

me

(AID

S): A

IDS

patie

nts

may

not

tole

rate

or r

espo

nd to

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im in

th

e sa

me

man

ner a

s no

n-AI

DS p

atie

nts.

The

inci

denc

e of

sid

e ef

fect

s, p

artic

ular

ly ra

sh, f

ever

, leu

kope

nia

and

elev

ated

am

inot

rans

fera

se (t

rans

amin

ase)

val

ues,

with

sul

fam

etho

xazo

le a

nd tr

imet

hopr

im th

erap

y in

AID

S pa

tient

s w

ho a

re b

eing

tre

ated

for P

neum

ocys

tis c

arin

ii pn

eum

onia

has

bee

n re

porte

d to

be

grea

tly in

crea

sed

com

pare

d w

ith th

e in

cide

nce

norm

ally

ass

ocia

ted

with

the

use

of s

ulfa

met

hoxa

zole

and

trim

etho

prim

in n

on-A

IDS

patie

nts.

The

inci

denc

e of

hy

perk

alem

ia a

ppea

rs to

be

incr

ease

d in

AID

S pa

tient

s re

ceiv

ing

sulfa

met

hoxa

zole

and

trim

etho

prim

. Adv

erse

effe

cts

are

gene

rally

less

sev

ere

in p

atie

nts

rece

ivin

g su

lfam

etho

xazo

le a

nd tr

imet

hopr

im fo

r pro

phyl

axis

. A h

isto

ry o

f mild

into

lera

nce

to s

ulfa

met

hoxa

zole

and

trim

etho

prim

in A

IDS

patie

nts

does

not

app

ear t

o pr

edic

t int

oler

ance

of s

ubse

quen

t sec

onda

ry

prop

hyla

xis.

6 Ho

wev

er, i

f a p

atie

nt d

evel

ops

skin

rash

or a

ny s

ign

of a

dver

se re

actio

n, th

erap

y w

ith s

ulfa

met

hoxa

zole

and

tri

met

hopr

im s

houl

d be

reev

alua

ted

(see

WAR

NING

S).

High

dos

age

of tr

imet

hopr

im, a

s us

ed in

pat

ient

s w

ith P

neum

ocys

tis c

arin

ii pn

eum

onia

, ind

uces

a p

rogr

essi

ve b

ut

reve

rsib

le in

crea

se o

f ser

um p

otas

sium

con

cent

ratio

ns in

a s

ubst

antia

l num

ber o

f pat

ient

s. E

ven

treat

men

t with

re

com

men

ded

dose

s m

ay c

ause

hyp

erka

lem

ia w

hen

trim

etho

prim

is a

dmin

iste

red

to p

atie

nts

with

und

erly

ing

diso

rder

s of

po

tass

ium

met

abol

ism

, with

rena

l ins

uffic

ienc

y, o

r if d

rugs

kno

wn

to in

duce

hyp

erka

lem

ia a

re g

iven

con

com

itant

ly. C

lose

m

onito

ring

of s

erum

pot

assi

um is

war

rant

ed in

thes

e pa

tient

s.

Durin

g tre

atm

ent,

adeq

uate

flui

d in

take

and

urin

ary

outp

ut s

houl

d be

ens

ured

to p

reve

nt c

ryst

allu

ria. P

atie

nts

who

are

"s

low

ace

tyla

tors

" may

be

mor

e pr

one

to id

iosy

ncra

tic re

actio

ns to

sul

fona

mid

es.


920 Avenue R Bldg. #200 Trimethoprim OS, USP …...Hi-Tech Pharmacal Co., Inc. 16oz....

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Transcript of 920 Avenue R Bldg. #200 Trimethoprim OS, USP …...Hi-Tech Pharmacal Co., Inc. 16oz....