40-9068
(morphine sulfate extended-release) Capsules
KADIAN CII
Revised –March 2007
KADIAN 10 mg Capsules
ules
ules
ules
KADIAN 80 mg Capsules
 100 mg Capsules
II controlled
substance, with an abuse liability similar to other opioid analgesics. KADIAN® can be
it. This should be
he physician or
suse, abuse or diversion.
uous, around-the-
-TOLERANT
capsules may
cause fatal respiratory depression when administered to patients not already tolerant to
opioids. KADIAN CAPSULES ARE TO BE SWALLOWED WHOLE OR
. THE
USHED, OR
DISSOLVED DUE TO THE RISK OF RAPID RELEASE AND ABSORPTION OF A
KADIAN 20 mg Caps
KADIAN 30 mg Caps
KADIAN 50 mg Caps
KADIAN 60 mg Capsules
KADIAN
KADIAN 200 mg Capsules
WARNING:
KADIAN® contains morphine sulfate, an opioid agonist and a Schedule
abused in a manner similar to other opioid agonists, legal or illic
considered when prescribing or dispensing KADIAN® in situations where t
pharmacist is concerned about an increased risk of mi
KADIAN capsules are an extended-release oral formulation of morphine sulfate
indicated for the management of moderate to severe pain when a contin
clock opioid analgesic is needed for an extended period of time.
KADIAN Capsules are NOT for use as a prn analgesic.
KADIAN® 100 mg and 200 mg Capsules ARE FOR USE IN OPIOID
PATIENTS ONLY. Ingestion of these capsules or of the pellets within the
high doses of
THE CONTENTS OF THE CAPSULES SPRINKLED ON APPLE SAUCE
PELLETS IN THE CAPSULES ARE NOT TO BE CHEWED, CR
POTENTIALLY FATAL DOSE OF MORPHINE.
DESCRIPTION
KADIAN® (morphine sulfate) capsules are an opioid analgesic supplied in 10 mg, 20 mg, 30
mg, 50 mg, 60 mg, 80 mg, 100 mg, and 200 mg strengths for oral administration.
Chemically, morphine sulfate is 7,8-didehydro-4,5 α- epoxy-17-methyl-morphinan-3,6 α- diol
sulfate (2:1) (salt) pentahydrate and has the following structural formula:
1
Morphine sulfate is an odorless, white, crystalline powder with a bitter taste and a m
weight of 758 (as the sulfate). It has a solubility of 1 in 21 parts of water and 1
alcohol, but is practica
olecular
in 1000 parts of
lly insoluble in chloroform or ether. The octanol: water partition
coefficient of morphine is 1.42 at physiologic pH and the pK is 7.9 for the tertiary nitrogen
0 mg, 60 mg,
ingredients
r,
shells contain
&C red #28,
FD&C blue #1 (10 mg), D&C yellow #10 (20 mg), FD&C red #3, FD&C blue #1 (30 mg), D&C
C blue #1 (50 mg), D&C red #28, FD&C red #40, FD&C blue #1
#10, FD&C
thetic opioid
ding analgesia,
ointestinal motility,
utic and its adverse effects by interaction with one or more
a pure
and
duce analgesia.
i.e., sleepiness
ever, specific
ve been
expression of
brainstem
respiratory centers. The mechanism of respiratory depression involves a reduction in the
responsiveness of the brainstem respiratory centers to increases in carbon dioxide tension, and to
electrical stimulation. Morphine depresses the cough reflex by direct effect on the cough center
in the medulla. Antitussive effects may occur with doses lower than those usually required for
analgesia. Morphine causes miosis, even in total darkness, and little tolerance develops to this
effect. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine
lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis
b
(mostly ionized at pH 7.4).
Each KADIAN extended-release capsule contains either 10 mg, 20 mg, 30 mg, 5
80 mg, 100 mg, or 200 mg of Morphine Sulfate USP and the following inactive
common to all strengths: hypromellose, ethylcellulose, methacrylic acid copolyme
polyethylene glycol, diethyl phthalate, talc, corn starch, and sucrose. The capsule
gelatin, silicon dioxide, sodium lauryl sulfate, titanium dioxide, and black ink, D
red #28, FD&C red #40, FD&
(60 mg), FD&C blue #1, FD&C red #40, FD&C yellow #6 (80 mg), D&C yellow
blue #1 (100 mg), black iron oxide, yellow iron oxide, red iron oxide (200 mg).
CLINICAL PHARMACOLOGY
Morphine is a natural product that is the prototype for the class of natural and syn
analgesics. Opioids produce a wide spectrum of pharmacologic effects inclu
dysphoria, euphoria, somnolence, respiratory depression, diminished gastr
altered circulatory dynamics, histamine release and physical dependence.
Morphine produces both its therape
classes of specific opioid receptors located throughout the body. Morphine acts as
agonist, binding with and activating opioid receptors at sites in the peri-aqueductal
peri-ventricular grey matter, the ventro-medial medulla and the spinal cord to pro
Effects on the Central Nervous System
The principal actions of therapeutic value of morphine are analgesia and sedation (
and anxiolysis). The precise mechanism of the analgesic action is unknown. How
CNS opiate receptors and endogenous compounds with morphine-like activity ha
identified throughout the brain and spinal cord and are likely to play a role in the
analgesic effects. Morphine produces respiratory depression by direct action on
2
rather than miosis may be seen with worsening hypoxia in the setting of KADIAN® overdose
(See OVERDOSAGE).
causes a
ch and
actions are
n are decreased, while tone is increased to the
point of spasm. The end result is constipation. Morphine can cause a marked increase in biliary
 of the sphincter of Oddi.
ich may result in orthostatic hypotension or
syncope. Release of histamine may be induced by morphine and can contribute to
potension. Manifestations of histamine release and/or peripheral vasodilation
d eyes and sweating.
ics
tions are related
nt individuals,
actors and are not generally useful as a guide to the
y be 10-50 times as
ate dose for opioid-naive individuals. Dosages of morphine
should be chosen and must be titrated on the basis of clinical evaluation of the patient and the
therapeutic and adverse effects.
tate, a lower Cmax and a
sulfate that
rations.
ity is primarily due to morphine. One metabolite, morphine-6-glucuronide, has
barrier.
the same for
elease formulations, although the time to peak blood level (Tmax) will be
longer and the Cmax will be lower for formulations that delay the release of morphine in the
gastrointestinal tract.
Elimination of morphine is primarily via hepatic metabolism to glucuronide metabolites (55 to
65%) which are then renally excreted. The terminal half-life of morphine is 2 to 4 hours,
however, a longer term half-life of about 15 hours has been reported in studies where blood has
been sampled up to 48 hours.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Gastric, biliary and pancreatic secretions are decreased by morphine. Morphine
reduction in motility associated with an increase in tone in the antrum of the stoma
duodenum. Digestion of food in the small intestine is delayed and propulsive contr
decreased. Propulsive peristaltic waves in the colo
tract pressure as a result of spasm
Effects on the Cardiovascular System
Morphine produces peripheral vasodilation wh
opioid-induced hy
may include pruritus, flushing, re
Pharmacodynam
Plasma Level-Analgesia Relationships
In any particular patient, both analgesic effects and plasma morphine concentra
to the morphine dose.
While plasma morphine-efficacy relationships can be demonstrated in non-tolera
they are influenced by a wide variety of f
clinical use of morphine. The effective dose in opioid-tolerant patients ma
great (or greater) than the appropri
balance between
For any fixed dose and dosing interval, KADIAN® will have, at steady-s
higher Cmin than conventional morphine.
Pharmacokinetics
KADIAN capsules contain polymer coated extended-release pellets of morphine
release morphine significantly more slowly than from conventional oral prepa
KADIAN activ
been shown to have analgesic activity, but does not readily cross the blood-brain
Following oral administration of morphine, the extent of absorption is essentially
immediate or extended-r
3
The single-dose pharmacokinetics of KADIAN are linear over the dosage ran
mg. The single dose and multipl
ge of 30 to 100
e dose pharmacokinetic parameters of KADIAN in normal
volunteers are summarized in Table 1.
Table 1: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose
study in normal volunteers and a multiple dose study in patients with cancer pain.
Regimen/ AUC#,+ Cmax+ Tmax Cmin+ Fluctuation*
Dosage Form (ng.h/mL) (ng/mL) (h) (ng/mL)
Single Dose (n=24)
KADIAN Capsule 271.0 (19.4) 15.6 (24.4) 8.6 (41.1) na^ na
Tablet 304.3 (19 ) 30.5 32.1) 2 5 (52.6) na
Morphine Solution 362.4 (42.6) 64.4 (38.2) 0.9 (55.8) na na
8 37.3 (37.7) 10.3 (32.2) 9.9 (52.3) 3.0 (45.5)
lease Tablet q12h 457.3 (40.2) 36.9 (42.0) 4.4 (53.0) 7.6 (60.3) 4.1 (51.5)
Extended-Release .1 ( . na
Multiple Dose (n=24)
KADIAN Capsule q24h 500.9 (3 .6)
Extended-Re
# For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady state
dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours
mately 50% of the morphine
llowing the
on average,
As with most forms of oral morphine, because of pre-systemic elimination, only
about 20 to 40% of the administered dose reaches the systemic circulation.
+ For single
* Steady-state fluctuation in plasma concentrations = Cmax-Cmin/Cmin
^ Not applicable
Absorption
Following the administration of oral morphine solution, approxi
absorbed reaches the systemic circulation within 30 minutes. However, fo
administration of an equal amount of KADIAN to healthy volunteers, this occurs,
after 8 hours.
Food Effects: While concurrent administration of food slows the rate of absorptio
KADIAN, the extent of absorption is not affected and KADIAN can be adminis
regard to meals.
n of
tered without
Steady State: When KADIAN is given on a fixed dosing regimen to patients with chronic pain
due to malignancy, steady state is achieved in about two days. At steady state, KADIAN will
have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution
and some other extended-release preparations (see Graph 1).
4
Graph 1 (Study # MOB-1/90 trations for
se morphine
tion (every 4
 concentrations are normalized to 100 mg
every 24 hours, (n=24).
 had a
ma e-daily
dosage (see
more
s compared
to norma ons).
Graph 2 (Study # a morphine
orphine
 concentrations are
): Mean steady state plasma morphine concen
KADIAN (twice a day), extended-relea
tablet (twice a day) and oral morphine solu
hours); plasma
When given once-daily (every 24 hours) to 24 patients with malignancy, KADIAN
similar C and higher C at steady state in clinical usage, when compared

x min to twic
Graph 2 and Table 1). Druggravely
ill patients, and may r a
l volunteers (see Ger i
MOR-9/92): Dose normalized mean steady state plasm
concentrations for KADIAN (once a day), and an
equivalent dose of a 12-hour, extended-release m
tablet given twice a day. Plasma
normalized to 100 mg every 24 hours, (n=24).
(every 12 hours) extended-release morphine tablets, given at an equivalent total daily
disease interactions are frequently seen in the older and
esult in both altered absorption and reduced clearance
iatric, Hepatic Failure, and Renal Insufficiency sect
5
Distribution
Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, in
spleen and brain. The volume of distribution of morphine is approximately 3 to 4 L
Morphine is 30 to 35% reversibly bound to plasma proteins. Although the prim
of morphine is in the CNS, only small quantities
testinal tract, lungs,
/kg.
ary site of action
pass the blood-brain barrier. Morphine also
crosses the placental membranes (see PRECAUTIONS - Pregnancy) and has been found in
k (see PRECAUTIONS - Nursing Mothers).
glucuronic
-3-etheral sulfate.
all practical purposes,
6G (about 5 to
thy subjects and cancer patients have shown that the glucuronide
metabolite to morphine mean molar ratios (based on AUC) are similar after both single doses
tablets and
morphine sulfate solution.
gonist and
f the dose is
bolites is
% of
administered morphine is excreted in the feces.
The mean adult plasma clearance is about 20-30 mL/minute/kg. The effective terminal half-life
of morphine after IV administration is reported to be approximately 2.0 hours. Longer plasma
sampling in some studies suggests a longer terminal half-life of morphine of about 15 hours.
breast mil
Metabolism
The major pathway of the detoxification of morphine is conjugation, either with Dacid
in the liver to produce glucuronides or with sulfuric acid to give morphine
Although a small fraction (less than 5%) of morphine is demethylated, for
virtually all morphine is converted to glucuronide metabolites including
morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M
15%). Studies in heal
and at steady state for KADIAN, 12-hour extended-release morphine sulfate
M3G has no significant analgesic activity. M6G has been shown to have opioid a
analgesic activity in humans.
Excretion
Approximately 10% of morphine dose is excreted unchanged in the urine. Most o
excreted in the urine as M3G and M6G. A small amount of the glucuronide meta
excreted in the bile and there is some minor enterohepatic cycling. Seven to 10
6
Special Populations
Geriatric: The elderly may have increased sensitivity to morphine and may achiev
more variable serum levels than younger patients. In adults, the duration of
progressively with age, though the degree of analgesia remains unchanged. K
pharmacokinetics have not been inves
e higher and
analgesia increases
ADIAN
tigated in elderly patients (>65 years) although such
a morphine
is about 2.5:1. The amount of morphine received by the infant depends on the
maternal plasma concentration, amount of milk ingested by the infant, and the extent of first pass
d decreased
clearance of morphine and its
elimination half-life begin to approach adult values by the second month of life. Pediatric
ar to adults,
NS - Pediatric Use).
strated in the
c data from clinical studies.
en intravenous
ts (1852 +
patients were included in the clinical studies.
Nursing Mothers: Morphine is excreted in the maternal milk, and the milk to plasm
AUC ratio
metabolism.
Pediatric: Infants under 1 month of age have a prolonged elimination half-life an
clearance relative to older infants and pediatric patients. The
patients old enough to take capsules should have pharmacokinetic parameters simil
dosed on a per kilogram basis (see PRECAUTIO
Gender: No meaningful differences between male and female patients were demon
analysis of the pharmacokineti
Race: Pharmacokinetic differences due to race may exist. Chinese subjects giv
morphine in one study had a higher clearance when compared to caucasian subjec
mL/min versus 1495 + 80 mL/min).
 116
Hepatic Failure: The pharmacokinetics of morphine were found to be significa
individuals with alcoholic cirrhosis. The clearance was found to decrease with
increase in half-life. The M3G and M6G to morphine plasm
ntly altered in
a corresponding
a AUC ratios also decreased in these
patients indicating a decrease in metabolic activity.
al failure patients.
ance is decreased. The metabolites, M3G and M6G accumulate
e
pharmacodynamic, not pharmacokinetic (see PRECAUTIONS - Drug Interactions).
INDICATIONS AND USAGE
KADIAN Capsules are an extended-release oral formulation of morphine sulfate indicated for
the management of moderate to severe pain when a continuous, around-the-clock opioid
analgesic is needed for an extended period of time (see CLINICAL PHARMACOLOGY).
KADIAN® Capsules are NOT intended for use as a prn analgesic.
Renal Insufficiency: The pharmacokinetics of morphine are altered in ren
AUC is increased and clear
several fold in renal failure patients compared with healthy subjects.
Drug-Drug Interactions: The known drug interactions involving morphine ar
7
KADIAN® is not indicated for pain in the immediate postoperative period (the
following surgery), or if the pain is mild or not expected to persist for an extende
time. KADIAN is only indicated for postoperative use if the patient is already re
drug prior to surgery or if the postoperative pain is expected to be moderate
first 12-24 hours
d period of
ceiving the
to severe and persist
for an extended period of time. Physicians should individualize treatment, moving from
esics as appropriate. (See American Pain Society guidelines.)
ine, morphine
indicated.
ve equipment
or in unmonitored settings), and in patients with acute or severe bronchial asthma or hypercarbia.
paralytic ileus.
d, or
to rapid release
OLERANT
sion when
to opioids.
ld be
scribed, as
cal consequences, including death.
bstance. Opioid
agonists have the potential for being abused and are sought by drug abusers and people with
legal or illicit. This should
hen prescribing or dispensing KADIAN® in situations where the physician or
uct will
uncontrolled delivery of the opioid and pose a significant risk to the abuser that
could result in overdose and death (see WARNINGS and DRUG ABUSE AND
DEPENDENCE)
Concerns about abuse, addiction, and diversion should not prevent the proper management of
pain. Healthcare professionals should contact their State Professional Licensing Board, or State
Controlled Substances Authority for information on how to prevent and detect abuse or diversion
of this product.
parenteral to oral analg
CONTRAINDICATIONS
KADIAN is contraindicated in patients with a known hypersensitivity to morph
salts or any of the capsule components, or in any situation where opioids are contra
This includes in patients with respiratory depression (in the absence of resuscitati
KADIAN is contraindicated in any patient who has or is suspected of having
WARNINGS
KADIAN® Capsules are to be swallowed whole and are not to be chewed, crushe
dissolved. Taking chewed, crushed, or dissolved KADIAN® Capsules leads
and absorption of a potentially fatal dose of morphine.
KADIAN® 100 mg and 200 mg Capsules ARE FOR USE IN OPIOID-T
PATIENTS ONLY. This capsule strength may cause fatal respiratory depres
ingested or administered to patients who are not previously exposed
Care should be taken in the prescribing of this capsule strength. Patients shou
instructed against use by individuals other than the patient for whom it was pre
such inappropriate use may have severe medi
Misuse, Abuse and Diversion of Opioids
KADIAN® contains morphine an opioid agonist and a Schedule II controlled su
addiction disorders and are subject to criminal diversion.
Morphine can be abused in a manner similar to other opioid agonists,
be considered w
pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
Abuse of KADIAN® by crushing, chewing, snorting or injecting the dissolved prod
result in the
8
Interactions with Alcohol and Drugs of Abuse
KADIAN® may be expected to have additive effects when used in conjunction w
other opioids, or illicit drugs that cause central nervous sys
ith alcohol,
tem depression because respiratory
sion, and profound sedation or coma may result.
piratory depression
nd those suffering from conditions
accompanied by hypoxia, hypercapnia, or upper airway obstruction (when even moderate
uctive pulmonary
spiratory reserve
epression. In
ic doses of morphine may increase airway resistance and
decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid
areful medical
nd secondary
may be markedly exaggerated in the presence of head
acranial lesions, or a pre-existing increase in intracranial pressure. KADIAN®
ure in patients
KADIAN may cause severe hypotension. There is an added risk to individuals whose ability
d volume, or a
. (See also
PRECAUTIONS - Drug Interactions.) KADIAN may produce orthostatic hypotension and
n to patients in
cardiac output and
blood pressure.
Interactions with other CNS Depressants
KADIAN® should be used with great caution and in reduced dosage in patients who are
concurrently receiving other central nervous system depressants including sedatives or
hypnotics, general anesthetics, phenothiazines, other tranquilizers, and alcohol because
respiratory depression, hypotension, and profound sedation or coma may result.
Gastrointestinal Obstruction
depression, hypoten
Impaired Respiration
Respiratory depression is the chief hazard of all morphine preparations. Res
occurs more frequently in elderly and debilitated patients, a
therapeutic doses may significantly decrease pulmonary ventilation).
KADIAN® should be used with extreme caution in patients with chronic obstr
disease or cor pulmonale, and in patients having a substantially decreased re
(e.g. severe kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory d
such patients, even usual therapeut
analgesics should be considered, and opioids should be employed only under c
supervision at the lowest effective dose.
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of morphine with carbon dioxide retention a
elevation of cerebrospinal fluid pressure
injury, other intr
produces effects which may obscure neurologic signs of further increases in press
with head injuries. Morphine should only be administered under such circumstances when
considered essential and then with extreme care.
Hypotensive Effect
to maintain blood pressure has already been compromised by a reduced bloo
concurrent administration of drugs such as phenothiazines or general anesthetics
syncope in ambulatory patients.
KADIAN, like all opioid analgesics, should be administered with cautio
circulatory shock, as vasodilation produced by the drug may further reduce
9
KADIAN should not be given to patients with gastrointestinal obstruction, parti
paralytic ileus, as there is a risk of the product remaining in the stomach for an exte
and the subsequent release of a bolus of morphine when normal gu
cularly
nded period
t motility is restored. As with
solid morphine formulations diarrhea may reduce morphine absorption.
Other
ely rare, cases of anaphylaxis have been reported.
k opioid
adjust the
nt, taking into account the patient's prior analgesic
treatment experience. Although it is clearly impossible to enumerate every consideration that is
given to the
have a narrow therapeutic index in certain patient populations, especially
ere the benefits
ntal state, and
e principles
isks associated
ollowing populations should be considered: the elderly or debilitated and
idism;
ency (e.g., Addison's Disease); CNS depression or coma; toxic psychosis;
prostatic hypertrophy, or urethral stricture; acute alcoholism; delirium tremens; kyphoscoliosis,
sorders.
Cordotomy
scheduled for cordotomy or other interruption of pain
edure and the
renteral short-acting opioids. In addition, the post-procedure titration of
analgesics for such patients should be individualized to avoid either oversedation or withdrawal
syndromes.
Use in Pancreatic/Biliary Tract Disease
KADIAN may cause spasm of the sphincter of Oddi and should be used with caution in
patients with biliary tract disease, including acute pancreatitis. Opioids may cause increases in
the serum amylase level.
other
Although extrem
PRECAUTIONS
General
KADIAN is intended for use in patients who require continuous, around-the-cloc
analgesia for an extended period of time. As with any potent opioid, it is critical to
dosing regimen for KADIAN for each patie
important to the selection of the initial dose of KADIAN, attention should be
points under DOSAGE AND ADMINISTRATION.
Opioid analgesics
when combined with CNS depressant drugs, and should be reserved for cases wh
of opioid analgesia outweigh the known risks of respiratory depression, altered me
postural hypotension.
Selection of patients for treatment with KADIAN® should be governed by the sam
that apply to the use of any potent opioid analgesics. Specifically, the increased r
with its use in the f
those with severe impairment of hepatic, pulmonary, or renal function; hypothyro
adrenocortical insuffici
or inability to swallow.
The administration of KADIAN® may obscure the diagnosis or clinical course in patients with
acute abdominal conditions.
KADIAN® may aggravate pre-existing convulsions in patients with convulsive di
Patients taking KADIAN who are
transmission pathways should have KADIAN ceased 24 hours prior to the proc
pain controlled by pa
10
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain a defined effect s
analgesia (in the absence of disease progression or other external factors)
is manifested by withdrawal symptoms after abrupt discontinuation of a drug o
administration of an
uch as
. Physical dependence
r upon
antagonist. Physical dependence and tolerance are not unusual during
all of the following:
p, including: irritability, anxiety, backache, joint pain,
g, diarrhea, or increased blood
s should not be abruptly discontinued (see DOSAGE AND
 derly or debilitated
n's disease;
myxedema; hypothyroidism; prostatic hypertrophy or urethral stricture.
nts with CNS
ive disorders.
KADIAN® may impair the mental and/or physical abilities needed to perform potentially
ch as driving a car or operating machinery. Patients must be cautioned
ts of KADIAN®
, phenothiazines, sedative/hypnotics and
alcohol (see Drug Interactions).
Information for Patients
uld be given the
f
1 aken only as
le (not
ned and the
entire contents sprinkled on a small amount of apple sauce immediately prior to ingestion.
KADIAN® capsules or the contents of the capsules must not be chewed or crushed due to a
risk of fatal overdose.
3. Patients should be advised that KADIAN® 100 mg and 200 mg Capsules are for use only in
opioid-tolerant patients. Special care must be taken to avoid accidental ingestion or use by
chronic opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis.
Other symptoms also may develo
weakness, abdominal cramps, insomnia, nausea, anorexia, vomitin
pressure, respiratory rate, or heart rate.
In general, opioid
ADMINISTRATION: Cessation of Therapy).
Special Risk Groups
KADIAN should be administered with caution, and in reduced dosages in el
patients; patients with severe renal or hepatic insufficiency; patients with Addiso
Caution should also be exercised in the administration of KADIAN to patie
depression, toxic psychosis, acute alcoholism and delirium tremens, and convuls
Driving and Operating Machinery
hazardous activities su
accordingly. Patients should also be warned about the potential combined effec
with other CNS depressants, including other opioids
If clinically advisable, patients receiving KADIAN, or their caregivers sho
ollowing information by the physician, nurse, or pharmacist:
. Patients should be advised that KADIAN® contains morphine and should be t
directed.
2. Patients should be advised that KADIAN capsules should be swallowed who
chewed, crushed, or dissolved). Alternately, KADIAN® capsules may be ope
11
individuals (including children) other than the patient for whom it was originally prescribed,
as such unsupervised use may have severe, even fatal, consequences.
4 of KADIAN should not be adjusted without
5 should be advised to report episodes of breakthrough pain and adverse experiences
occurring during therapy. Individualization of dosage is essential to make optimal use of this
6 l ability
ing, operating
should refrain
ffected.
7 should be advised that KADIAN® should not be taken with alcohol or other CNS
depressants (sleeping medication, tranquilizers) except by the orders of the prescribing
serious injury
gnant, should
herapy with
9 receiving treatment with KADIAN® for
iate to taper
ecipitating
mptoms. Their prescribing healthcare provider should provide a dose schedule
to accomplish a gradual discontinuation of the medication.
1 ould protect
it from theft, and it should never be given to anyone other than the individual for whom it
1 dvised that severe constipation could occur as a result of taking
KADIAN® and appropriate laxatives, stool softeners and other appropriate treatments should
reach of
ld be destroyed by
flushing down the toilet.
Drug Interactions
CNS Depressants: Morphine should be used with great caution and in reduced dosage in patients
who are concurrently receiving other central nervous system (CNS) depressants including
sedatives, hypnotics, general anesthetics, antiemetics, phenothiazines, other tranquilizers and
alcohol because of the risk of respiratory depression, hypotension and profound sedation or
. Patients should be advised that the dose
consulting the prescribing health care provider.
. Patients
medication.
. Patients should be advised that KADIAN® may impair mental and/or physica
required for the performance of potentially hazardous tasks (e.g., driv
machinery). Patients started on KADIAN or whose dose has been changed
from dangerous activity until it is established that they are not adversely a
. Patients
healthcare provider because dangerous additive effects may occur resulting in
or death.
8. Women of childbearing potential who become or are planning to become pre
consult their prescribing healthcare provider prior to initiating or continuing t
KADIAN®.
. Patients should be advised that if they have been
more than a few weeks and cessation of therapy is indicated, it may be appropr
the KADIAN® dose, rather than abruptly discontinue it, due to the risk of pr
withdrawal sy
0. Patients should be advised that KADIAN® is a potential drug of abuse. They sh
was prescribed.
1. Patients should be a
be initiated from the beginning of opioid therapy.
12. Patients should be instructed to keep KADIAN® in a secure place out of the
children. When KADIAN® is no longer needed, the unused capsules shou
12
coma. When such combined therapy is contemplated, the initial dose of one or both agents
should be reduced by at least 50%.
cular blocking action of skeletal
, pentazocine,
has received
gonist analgesic such as KADIAN®. In
this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of KADIAN®
Oxidase Inhibitors (MAOIs): MAOIs have been reported to intensify the effects of
at least one opioid drug causing anxiety, confusion and significant depression of respiration or
s of stopping
sion when a
inistered morphine and cimetidine.
iuretics by inducing the release of antidiuretic
f the sphincter
have not been
s have
duces
rosophila.
o in human T-cells, increasing the DNA
ation. In vivo, morphine was mutagenic in the mouse micronucleus test and induced
s and murine lymphocytes. Chronic opioid abusers (e.g.,
owever, the
nd in heroin users
Teratogenic effects of morphine have been reported in the animal literature. High parental doses
rimester were teratogenic in neurological, soft and skeletal tissue. The
abnormalities included encephalopathy and axial skeletal fusions. These doses were often
maternally toxic and were 0.3 to 3-fold the maximum recommended human dose (MRHD) on a
mg/m2
 basis. The relative contribution of morphine-induced maternal hypoxia and malnutrition,
each of which can be teratogenic, has not been clearly defined. Treatment of male rats with
approximately 3-fold the MRHD for 10 days prior to mating decreased litter size and viability.
Nonteratogenic Effects
Muscle Relaxants: KADIAN® may enhance the neuromus
relaxants and produce an increased degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e.
nalbuphine, and butorphanol) should be administered with caution to a patient who
or is receiving a course of therapy with a pure opioid a
and/or may precipitate withdrawal symptoms in these patients.
Monoamine
coma. KADIAN should not be used in patients taking MAOIs or within 14 day
such treatment.
Cimetidine: There is an isolated report of confusion and severe respiratory depres
hemodialysis patient was concurrently adm
Diuretics: Morphine can reduce the efficacy of d
hormone. Morphine may also lead to acute retention of urine by causing spasm o
of the bladder, particularly in men with prostatism.
Carcinogenicity/Mutagenicity/Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of morphine
conducted. There are no reports of carcinogenic effects in humans. In vitro studie
reported that morphine is non-mutagenic in the Ames test with Salmonella, and in
chromosomal aberrations in human leukocytes and lethal mutation induction in D
Morphine was found to be mutagenic in vitr
fragment
chromosomal aberrations in spermatid
heroin abusers) and their offspring display higher rates of chromosomal damage. H
rates of chromosomal abnormalities were similar in nonexposed individuals a
enrolled in long term opioid maintenance programs.
Pregnancy
Teratogenic Effects (Pregnancy Category C)
during the second t
13
Morphine given subcutaneously, at non-maternally toxic doses, to rats during the
with approximately 0.15-fold the MRHD caused reversible reductions in brai
volume, and testes size and body weight in the offspring, and decreased fertili
offspring. The offspring of rats and hamsters treated orally or intraperitoneally t
pregnancy with 0.04- to 0.3-fold the MRHD of morphine have demonstrated dela
motor and sexual maturation and decreased male
third trimester
n and spinal cord
ty in female
hroughout
yed growth,
fertility. Chronic morphine exposure of fetal
animals resulted in mild withdrawal, altered reflex and motor skill development, and altered
sulfate in human
ally exposed to
over the first
sing mothers are more often small for gestational age,
have a decreased ventilatory response to CO2 and increased risk of sudden infant death
IAN® should only be used during pregnancy if the need for strong opioid
to labor, where
. Occasionally,
e strength,
ct is not consistent and may be
offset by an increased rate of cervical dilatation which tends to shorten labor. Neonates whose
ns of
hould be
The newborn
stations of NWS
ability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting,
t loss, and failure to gain weight. The onset, duration, and severity of the
of mother’s last
reatment of this
egoric or
others
mptoms can
stopped.
Because of the potential for adverse reactions in nursing infants from KADIAN®, a decision
should be made whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
The safety of KADIAN®, both the entire capsule and the pellets sprinkled on apple sauce, have
not been directly investigated in pediatric patients below the age of 18 years. The range of doses
responsiveness to morphine that persisted into adulthood.
There are no well-controlled studies of chronic in utero exposure to morphine
subjects. However, uncontrolled retrospective studies of human neonates chronic
other opioids in utero, demonstrated reduced brain volume which normalized
month of life. Infants born to opioid-abu
syndrome. KAD
analgesia justifies the potential risk to the fetus.
Labor and Delivery
KADIAN® is not recommended for use in women during and immediately prior
shorter acting analgesics or other analgesic techniques are more appropriate
opioid analgesics may prolong labor through actions which temporarily reduce th
duration and frequency of uterine contractions. However, this effe
mothers received opioid analgesics during labor should be observed closely for sig
respiratory depression. A specific opioid antagonist, such as naloxone or nalmefene, s
available for reversal of opioid-induced respiratory depression in the neonate.
Neonatal Withdrawal Syndrome
Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus.
may experience subsequent neonatal withdrawal syndrome (NWS). Manife
include irrit
diarrhea, weigh
disorder differ based on such factors as the addictive drug used, time and amount
dose, and rate of elimination of the drug from the newborn. Approaches to the t
syndrome have included supportive care and, when indicated, drugs such as par
phenobarbital.
Nursing M
Low levels of morphine sulfate have been detected in human milk. Withdrawal sy
occur in breast-feeding infants when maternal administration of morphine sulfate is
14
available is not suitable for the treatment of very young pediatric patients or tho
old enough to take capsu
se who are not
les safely. The apple sauce sprinkling method is not an appropriate
alternative for these patients.
65 and over to
linical
younger patients.
uld be cautious, usually starting at the low end
of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
t may be associated with KADIAN® therapy in clinical use are
those observed with other opioid analgesics and include: respiratory depression, respiratory
see
also typical
nds on the clinical
vidual. They
f these
ency of these
itiation of therapy may be minimized by careful individualization of starting
idance of large rapid swings in plasma concentrations of the
py is continued
remain troublesome
y disappears
ostural
, and has been associated with syncope
and falls in non-tolerant patients started on opioids.
should include:
poxia or
hypercapnia due to exacerbated respiratory failure, intolerance to the dose used (especially in
d the patient's general condition.
The dosage should be adjusted according to individual needs, but additional care should be used
in the selection of initial doses for the elderly patient, the cachectic or gravely ill patient, or in
patients not already familiar with opioid analgesic medications to prevent excessive sedation at
the onset of treatment.
Management of Nausea and Vomiting
Geriatric Use
Clinical studies of KADIAN® did not include sufficient numbers of subjects aged
determine whether they respond differently from younger subjects. Other reported c
experience has not identified differences in responses between the elderly and
In general, dose selection for an elderly patient sho
function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Serious adverse reactions tha
arrest, apnea, circulatory depression, cardiac arrest, hypotension, and/or shock (
OVERDOSAGE, WARNINGS).
The less severe adverse events seen on initiation of therapy with KADIAN® are
opioid side effects. These events are dose dependent, and their frequency depe
setting, the patient's level of opioid tolerance, and host factors specific to the indi
should be expected and managed as a part of opioid analgesia. The most frequent o
include drowsiness, dizziness, constipation and nausea. In many cases, the frequ
events during in
dosage, slow titration, and the avo
opioid. Many of these adverse events, will cease or decrease as KADIAN® thera
and some degree of tolerance is developed, but others may be expected to
throughout therapy.
Management of Excessive Drowsiness
Most patients receiving KADIAN® will experience initial drowsiness. This usuall
within 3-5 days and is not a cause of concern unless it is excessive, or accompanied by
unsteadiness or confusion. Dizziness and unsteadiness may be associated with p
hypotension, particularly in elderly or debilitated patients
Excessive or persistent sedation should be investigated. Factors to be considered
concurrent sedative medications, the presence of hepatic or renal insufficiency, hy
older patients), disease severity an
15
Nausea and vomiting are common after single doses of KADIAN® or as an early u
effect of chronic opioid therapy. The prescription of a suitable antiemetic should
with the awareness that sedation may result (see Drug Interactions). The frequenc
and vomiting usually decreases within a week
ndesirable
be considered,
y of nausea
or so but may persist due to opioid-induced gastric
often useful in such patients.
IAN®, on a
ts may become
constipating effects of opioids. Patients
must be cautioned accordingly and laxatives, softeners and other appropriate treatments should
ain the most common adverse events reported
by patients at least once during therapy were drowsiness (9%), constipation (9%), nausea (7%),
m KADIAN® or
were:
tal injury, fever, pain, chest pain, headache, diaphoresis,
chills, flu syndrome, back pain, malaise, withdrawal syndrome
or, facial
l thinking, abnormal dreams,
lethargy, depression, tremor, loss of concentration, insomnia, amnesia, paresthesia, agitation,
, euphoria,
secretion, gynecomastia
Gastrointestinal: Vomiting, anorexia, dysphagia, dyspepsia, diarrhea, abdominal pain, stomach
elayed gastric emptying, biliary colic
ia, edema
Respiratory: Hiccup, rhinitis, atelectasis, asthma, hypoxia, dyspnea, respiratory insufficiency,
voice alteration, depressed cough reflex, non-cardiogenic pulmonary edema
Skin and Appendages: Rash, decubitus ulcer, pruritus, skin flush
Special Senses: Amblyopia, conjunctivitis, miosis, blurred vision, nystagmus, diplopia
stasis. Metoclopramide is
Management of Constipation
Virtually all patients suffer from constipation while taking opioids, such as KAD
chronic basis. Some patients, particularly elderly, debilitated or bedridden patien
impacted. Tolerance does not usually develop for the
be used prophylactically from the beginning of opioid therapy.
Adverse Events Probably Related to KADIAN Administration
In clinical studies in patients with chronic cancer p
dizziness (6%), and anxiety (6%). Other less common side effects expected fro
seen in less than 3% of patients in the clinical studies
Body as a Whole: Asthenia, acciden
Cardiovascular: Tachycardia, atrial fibrillation, hypotension, hypertension, pall
flushing, palpitations, bradycardia, syncope
Central Nervous System: Confusion, dry mouth, anxiety, abnorma
vertigo, foot drop, ataxia, hypesthesia, slurred speech, hallucinations, vasodilation
apathy, seizures, myoclonus
Endocrine: Hyponatremia due to inappropriate ADH
atony disorder, gastro-esophageal reflux, d
Hemic & Lymphatic: Anemia, leukopenia, thrombocytopenia
Metabolic & Nutritional: Peripheral edema, hyponatrem
Musculoskeletal: Back pain, bone pain, arthralgia
16
Urogenital: Urinary abnormality, amenorrhea, urinary retention, urinary hesitancy, reduced
libido, reduced potency, prolonged labor
el, 4-week
5 with chronic, nonl
arm was included in
py were
usea (9%) and somnolence (3%). Other less common side effects
ts were vomiting, pruritus, dizziness, sedation, dry mouth,
KADIAN® is a mu-agonist opioid with an abuse liability similar to other opioid agonists
ed in analgesia
rders. Its
r in remission, is for
id analgesia.
es, and continued
a multidicts
and drug abusers. Drug-seeking tactics
include emergency calls or visits near the end of office hours, refusal to undergo appropriate
with prescriptions
ating
ong drug
hysical dependence and tolerance.
Physicians should be aware that addiction may not be accompanied by concurrent tolerance and
occur in the
es, often in
bination with other psychoactive substances. KADIAN®, like other opioids, has been
including
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy,
and proper dispensing and storage are appropriate measures that help to limit abuse of opioid
drugs.
KADIAN® is intended for oral use only. Abuse of chewed, crushed, or dissolved capsules
or pellets poses a hazard of overdose and death. This risk is increased with concurrent
abuse of alcohol and other substances. Due to the presence of talc as one of the excipients in
Post-marketing Adverse Events Probably Related to KADIAN®
The safety of KADIAN® has been evaluated in a randomized, prospective, open-lab
treatment period, post-marketing study consisting of 1418 patients ages 18-8
malignant pain (e.g., back pain, osteoarthritis, neuropathic pain). No contro
this study. The most common adverse events reported at least once during thera
constipation (12%), na
occurring in less than 3% of patien
headache, fatigue and rash.
DRUG ABUSE AND DEPENDENCE
and is a Schedule II controlled substance. KADIAN® and other opioids us
can be abused and are subject to criminal diversion.
KADIAN® is an opioid with no approved use in the management of addiction diso
proper usage in individuals with drug or alcohol dependence, either active o
the management of pain requiring opio
Drug addiction is characterized by compulsive use, use for non-medical purpos
use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing
disciplinary approach, but relapse is common.
“Drug-seeking” behavior is very common in ad
examination, testing or referral, repeated “loss” of prescriptions, tampering
and reluctance to provide prior medical records or contact information for other tre
physician(s). “Doctor shopping” to obtain additional prescriptions is common am
abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from p
symptoms of physical dependence in all addicts. In addition, abuse of opioids can
absence of true addiction and is characterized by misuse for non-medical purpos
com
diverted for non-medical use. Careful record-keeping of prescribing information,
quantity, frequency, and renewal requests is strongly advised.
17
capsules, parenteral abuse can be expected to result in local tissue necrosi
pulmonary granulomas, and increased risk of endocarditis and valvular heart
Parenteral drug a
s, infection,
injury.
buse is commonly associated with transmission of infectious diseases such
as hepatitis and HIV.
mnolence
skin, constricted
pupils, and, sometimes, pulmonary edema, bradycardia, hypotension and death. Marked
ations.
titution of
assisted or controlled ventilation. Gastric contents may need to be emptied to remove unabsorbed
are should be
ated charcoal.
in the management
ardiac arrest
piratory
uld be expected
to be less than the duration of action of KADIAN®, the patient must be carefully monitored until
ase and add to
n overdose
al or not
cturer of the product.
nt respiratory
d be administered
on KADIAN®.
acute
physically dependent on opioids, administration
hdrawal. The severity of the
ee of physical dependence and the dose of the
antagonist administered. Use of an opioid antagonist should be reserved for cases where such
treatment is clearly needed. If it is necessary to treat serious respiratory depression in the
physically dependent patient, administration of the antagonist should be begun with care and by
titration with smaller than usual doses of the antagonist.
DOSAGE AND ADMINISTRATION
KADIAN® may be administered once or twice daily.
OVERDOSAGE
Symptoms
Acute overdosage with morphine is manifested by respiratory depression, so
progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy
mydriasis rather than miosis may be seen due to severe hypoxia in overdose situ
Treatment
Primary attention should be given to the re-establishment of a patent airway and ins
drug when an extended-release formulation such as KADIAN® has been taken. C
taken to secure the airway before attempting treatment by gastric emptying or activ
Supportive measures (including oxygen, vasopressors) should be employed
of circulatory shock and pulmonary edema accompanying overdose as indicated. C
or arrhythmias may require cardiac massage or defibrillation.
The pure opioid antagonists, naloxone or nalmefene, are specific antidotes to res
depression which results from opioid overdose. Since the duration of reversal wo
spontaneous respiration is reliably re-established. KADIAN® will continue to rele
the morphine load for up to 24 hours after administration and the management of a
should be monitored accordingly. If the response to opioid antagonists is suboptim
sustained, additional antagonist should be given as directed by the manufa
Opioid antagonists should not be administered in the absence of clinically significa
or circulatory depression secondary to morphine overdose. Such agents shoul
cautiously to persons who are known, or suspected to be physically dependent
In such cases, an abrupt or complete reversal of opioid effects may precipitate an
abstinence syndrome.
Opioid Tolerant Individuals: In an individual
of the usual dose of the antagonist will precipitate an acute wit
withdrawal produced will depend on the degr
18
KADIAN® capsules should be swallowed whole. The pellets in KADIAN®
not be chewed, crushed, or di
capsules should
ssolved due to the risk of rapid release and absorption of a
potentially fatal dose of morphine.
tively, KADIAN® capsules may be administered as a sprinkle on apple sauce or through
a 16 French gastrostomy tube (see ALTERNATIVE METHODS OF ADMINISTRATION
-operatively for
the management of post-operative pain), or for pain in the immediate post-operative period
g the drug,
KADIAN® is only indicated for post-operative use if the patient is already receiving the
o severe and
Patients who are already receiving KADIAN® Capsules as part of ongoing analgesic therapy
propriate dosage adjustments are made considering the
the surgical
Initiating Therapy with KADIAN® Capsules
gement such as
eration of
odel Guidelines. Health care professionals should follow appropriate
ng into account the
lection of the initial dose of KADIAN®,
nd of opioid the patient has been taking previously;
alent dose of
on);
4) the general condition and medical status of the patient;
5) concurrent medication;
6) the type and severity of the patient's pain.
Care should be taken to use low initial doses of KADIAN® in patients who are not already
opioid-tolerant, especially those who are receiving concurrent treatment with muscle
relaxants, sedatives, or other CNS active medications (see PRECAUTIONS).
Alterna
section).
The 100 mg and 200 mg capsules are for use only in opioid-tolerant patients.
KADIAN® is not indicated for pre-emptive analgesia (administration pre
(the first 12 to 24 hours following surgery) for patients not previously takin
because its safety in these settings have not been established.
drug prior to surgery or if the postoperative pain is expected to be moderate t
persist for an extended period of time.
may be safely continued on the drug if ap
procedure, other drugs given, and the temporary changes in physiology caused by
intervention.
Physicians should individualize treatment using a progressive plan of pain mana
outlined by the World Health Organization, the American Pain Society and the Fed
State Medical Boards M
pain management principles of careful assessment and ongoing monitoring.
It is critical to adjust the dosing regimen for each patient individually, taki
patient's prior analgesic treatment experience. In the se
attention should be given to:
1) the total daily dose, potency and ki
2) the reliability of the relative potency estimate used to calculate the equiv
morphine needed (Note: potency estimates may vary with the route of administrati
3) the patient's degree of opioid experience and opioid tolerance;
19
During periods of changing analgesic requirements including initial titration, freq
communication is recomme
uent
nded between physician, other members of the healthcare team, the
patient, and the caregiver/family.
sted approaches
to what is actually a series of clinical decisions over time in the management of the pain of an
by administering
every 12 hours
e-a-day) or by administering the total daily oral morphine dose as KADIAN® capsules
every 12
s to KADIAN®
parenteral
valents in
cancer analgesia, there is substantial interpatient variation in the relative potency of different
patient's 24-
h te and manage
a
oral morphine to
al morphine three
e settings.
2 stematic
se types of analgesic substitutions. Therefore, specific
recommendations are not possible. Physicians are advised to refer to published relative
ral, it is safest to
alf of the estimated daily morphine demand as the initial dose, and to manage
inadequate analgesia by supplementation with immediate-release morphine. (See discussion
iate-release (shortnistration
of
Use of KADIAN® as the First Opioid Analgesic
There has been no evaluation of KADIAN® as an initial opioid analgesic in the management of
pain. Because it may be more difficult to titrate a patient to adequate analgesia using an
extended-release morphine, it is ordinarily advisable to begin treatment using an immediaterelease
morphine formulation.
Individualization of Dosage
The following dosing recommendations, therefore, can only be considered sugge
individual patient.
Conversion from Other Oral Morphine Formulations to KADIAN®
Patients on other oral morphine formulations may be converted to KADIAN®
one-half of the patient's total daily oral morphine dose as KADIAN® capsules
(twic
every 24 hours (once-a-day). KADIAN® should not be given more frequently than
hours.
Conversion from Parenteral Morphine or Other Parenteral or Oral Opioid
KADIAN® can be administered to patients previously receiving treatment with
morphine or other opioids. While there are useful tables of oral and parenteral equi
opioid drugs and formulations. For these reasons, it is better to underestimate the
our oral morphine requirement and provide rescue medication, than to overestima
n adverse event. The following general points should be considered:
1. Parenteral to Oral Morphine Ratio: It may take anywhere from 2-6 mg of
provide analgesia equivalent to 1 mg of parenteral morphine. A dose of or
times the daily parenteral morphine requirement may be sufficient in chronic us
. Other Parenteral or Oral Opioids to Oral Morphine Sulfate: There is lack of sy
evidence bearing on the
potency data, keeping in mind that such ratios are only approximate. In gene
give h
which follows.)
The first dose of KADIAN® may be taken with the last dose of any immed
acting) opioid medication due to the long delay until the peak effect after admi
KADIAN®.
20
The best use of opioid analgesics in the management of chronic malignan
pain is challenging, and is well described in materials published by the World H
Organization and the Agency for Health Care Policy and Research which are avai
Alpharma Branded Products Division Inc. upon request. KADIAN® is a thir
is most useful when the patient requires a constant level of opioid analgesia as a "f
"platform" from which to manage breakthrough pain. When a patient has reach
where comfort cannot be provided with a combination of n
t and non-malignant
ealth
lable from
d step drug which
loor" or
ed the point
on-opioid medications (NSAIDs and
acetaminophen) and intermittent use of moderate or strong opioids, the patient's total opioid
ily oral
al morphine
than everygh
pain
s, the dose may be supplemented with a small dose (less than 20% of the total daily dose)
of a short-acting analgesic. Patients who are excessively sedated after a once-a-day dose or who
to twice-a-day
y on the 10 mg or 20
ery-other-day.
ustment until
e analgesia and opioid side
and constipation. No guidance can be given as to the
y. In such
erapeutic endpoint is
Alternative Methods of Administration
ce were found to be
asting
c o have difficulty swallowing whole
ay benefit from this alternative method of administration.
room
temperature or cooler.
immediate
release of a potentially dangerous, even fatal dose of morphine.
wallowed.
5. Patients should consume entire portion and should not divide apple sauce into separate doses.
The entire capsule contents may alternatively be administered through a 16 French gastrostomy
tube.
1. Flush the gastrostomy tube with water to ensure that it is wet.
2. Sprinkle the KADIAN Pellets into 10 mL of water.
therapy should be converted into a 24 hour oral morphine equivalent.
KADIAN® should be started by administering one-half of the estimated total da
morphine dose every 12 hours (twice-a-day) or by administering the total daily or
dose every 24 hours (once-a-day). The dose should be titrated no more frequently
other-day to allow the patients to stabilize before escalating the dose. If breakthrou
occur
regularly experience inadequate analgesia before the next dose should be switched
dosing.
Patients who do not have a proven tolerance to opioids should be started onl
mg strength, and usually should be increased at a rate not greater than 20 mg ev
Most patients will rapidly develop some degree of tolerance, requiring dosage adj
they have achieved their individual best balance between baselin
effects such as confusion, sedation
recommended maximal dose, especially in patients with chronic pain of malignanc
cases the total dose of KADIAN® should be advanced until the desired th
reached or clinically significant opioid-related adverse reactions intervene.
In a study of healthy volunteers, KADIAN® pellets sprinkled over apple sau
bioequivalent to KADIAN® capsules swallowed whole with apple sauce under f
onditions. Other foods have not been tested. Patients wh
capsules or tablets m
1. Sprinkle the pellets onto a small amount of apple sauce. Apple sauce should be
2. The patient must be cautioned not to chew the pellets which could result in the
3. Use immediately.
4. Rinse mouth to ensure all pellets have been s
21
3 a swirling motion to pour the pellets and water into the gastrostomy tube through a
ater and pour this into the funnel.
5. Repeat rinsing until no pellets remain in the beaker.
THE ADMINISTRATION OF KADIAN PELLETS THROUGH A NASOGASTRIC
xt dose should
rough pain occurs
ideration should be
sing regimen a
ic may be given. As experience is gained,
adjustments in both dose and dosing interval can be made to obtain an appropriate balance
and opioid side effects. To avoid accumulation the dosing interval of
erapy
ses should be
ally
ulations
tions. Although for
s from morphine
xtended-release morphine tablets, the slower release of morphine from KADIAN®
results in reduced maximum and increased minimum plasma morphine concentrations than with
from KADIAN® to the same total daily dose of
at peak or
adjustments are
When converting a patient from KADIAN® to parenteral opioids, it is best to calculate an
lue. For
t taking
nteral
vide the estimated 24 hour parenteral dose into six divided doses (for a
four hour dosing interval), then halve this dose as an initial trial.
. Use
funnel.
4. Rinse the beaker with a further 10 mL of w
TUBE SHOULD NOT BE ATTEMPTED.
Considerations in the Adjustment of Dosing Regimens
If signs of excessive opioid effects are observed early in the dosing interval, the ne
be reduced. If this adjustment leads to inadequate analgesia, that is, if breakth
when KADIAN® is administered on an every 24 hours dosing regimen, cons
given to dosing every 12 hours. If breakthrough pain occurs on a 12 hour do
supplemental dose of a short-acting analges
between pain relief
KADIAN® should not be reduced below 12 hours.
Cessation of Th
When the patient no longer requires therapy with KADIAN® capsules, do
tapered gradually to prevent signs and symptoms of withdrawal in the physic
dependent patient.
Conversion from KADIAN® to Other Extended-Release Oral Morphine Form
KADIAN® is not bioequivalent to other extended-release morphine prepara
a given dose the same total amount of morphine is available from KADIAN® a
solution or e
shorter acting morphine products. Conversion
extended-release morphine preparations may lead to either excessive sedation
inadequate analgesia at trough and close observation and appropriate dosage
recommended.
Conversion from KADIAN® to Parenteral Opioids
equivalent parenteral dose, and then initiate treatment at half of this calculated va
example, to estimate the required 24 hour dose of parenteral morphine for a patien
KADIAN®, one would take the 24 hour KADIAN® dose, divide by an oral to pare
conversion ratio of 3, di
For example, to estimate the required parenteral morphine dose for a patient taking 360 mg of
KADIAN® a day, divide the 360 mg daily oral morphine dose by a conversion ratio of 1 mg of
parenteral morphine for every 3 mg of oral morphine. The estimated 120 mg daily parenteral
requirement is then divided into six 20 mg doses, and half of this, or 10 mg, is then given every 4
hours as an initial trial dose.
22
This approach is likely to require a dosage increase in the first 24 hours for many
recommended bec
patients, but is
ause it is less likely to cause overdose than trying to establish an equivalent
dose without titration.
er Schedule II
ine, like all opioids, is liable to diversion and misuse
and should be handled accordingly. Patients and their families should be instructed to flush any
Healthcare professionals should
thority for
sts of closed hard gelatin capsules containing polymer coated morphine sulfate
pellets that pose no known handling risk to health care workers. KADIAN® Capsules are liable
misuse both by the general public and health care workers, and should be
coated extended-release
paque body
57-410-11).
body printed
63857-322-11).
opaque body
(NDC 63857-325-11).
ue body printed with
50 mg. Capsules are supplied in bottles of 100 (NDC 63857-323-11).
pink opaque body printed with
ht orange opaque
7-412-11).
100 mg size 0 capsule, green opaque cap printed with KADIAN and green opaque body printed
857-324-11).
200 mg size 0 capsule, light brown opaque cap printed with KADIAN and light brown opaque
body printed with 200 mg. Capsules are supplied in bottles of 100 (NDC 63857-377-11).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Protect from light and
moisture.
Dispense in a sealed tamper-evident, childproof, light-resistant container.
Safety and Handling
KADIAN® Capsules contain morphine sulfate which is a controlled substance und
of the Controlled Substances Act. Morph
KADIAN® capsules that are no longer needed.
KADIAN® may be targeted for theft and diversion by criminals.
contact their State Professional Licensing Board or State Controlled Substances Au
information on how to prevent and detect abuse or diversion of this product.
KADIAN® consi
to diversion and
handled accordingly.
HOW SUPPLIED
KADIAN® capsules contain white to off-white or tan colored polymer
pellets of morphine sulfate and are available in eight dose strengths:
10 mg size 4 capsule, light blue opaque cap printed with KADIAN and light blue o
printed with 10 mg. Capsules are supplied in bottles of 100 (NDC 638
20 mg size 4 capsule, yellow opaque cap printed with KADIAN and yellow opaque
with 20 mg. Capsules are supplied in bottles of 100 (NDC
30 mg size 4 capsule, blue violet opaque cap printed with KADIAN and blue violet
printed with 30 mg. Capsules are supplied in bottles of 100
50 mg size 2 capsule, blue opaque cap printed with KADIAN and blue opaq
60 mg size 1 capsule, pink opaque cap printed with KADIAN and
60 mg. Capsules are supplied in bottles of 100 (NDC 63857-326-11).
80 mg size 0 capsule, light orange opaque cap printed with KADIAN and lig
body printed with 80 mg. Capsules are supplied in bottles of 100 (NDC 6385
with 100 mg. Capsules are supplied in bottles of 100 (NDC 63
23
24
CAUTION: DEA Order Form Required.
KADIAN® is a registered trademark. KADIAN is a trademark owned by Alpharma Branded
Manufactured ded Products Division Inc.
nd Avenue
J 08854
LC
200 Elmora Avenue
Elizabeth, NJ 07207 USA
40-9068
Products Division Inc.
for: Alpharma Bran
One New Engla
Piscataway, N
by: Actavis Elizabeth L
Revised –March 2007
Each capsule contains: 10 mg
morphine sulfate as extended-release pellets.
Usual Dosage: See accompanying
prescribing information.
The pellets from KADIAN® capsules should
NOT be chewed, crushed or dissolved.
Warning: As with all medication, keep out
of the reach of children.
Dispense in a sealed, tamper-evident,
childproof, light-resistant container.
Store at 25°C (77°F); excursions permitted
to 15°-30°C (59°-86°F). Protect from light
and moisture.
Manufactured for:
Alpharma Branded Products Division Inc.
One New England Avenue
Piscataway, NJ 08854
by: Actavis Elizabeth LLC, 200 Elmora Avenue
Elizabeth, NJ 07207 USA Rev. 12/06
Lot No.:
.5"
Unvarnished
Area
PANTONE
541
PANTONE
369
BLACK
PAXTON ADVERTISING
31 Wesley Court, Eatontown, NJ 07724
732-935-9727 Fax 732-935-9730
REGULATORY REVIEW: DATE
APPROVED REJECTED
(Please Circle)
UPC CODE
SIZE: 90%
BWR: -.001
SPOT COLORS
SIZE: 1.5 x 4.5
Illustrator 10 with Linked Photoshop Image
ARTWORK BY: Carol Comins
DATE: 12/14/06
SUBMISSION: 2
NDC 63857-410-11
100 Capsules
PANTONE
290
10 mg
STRENGTH
NEW
N
3 9 63857-410-11