WARNINGS
KADIAN
®
Capsules are to be swallowed whole
and are not to be chewed, crushed, or dissolved. Taking chewed, crushed, or
dissolved KADIAN
®
Capsules leads to rapid release and absorption of a potentially
fatal dose of morphine.
KADIAN
®
100 mg and 200 mg Capsules ARE FOR
USE IN OPIOID-TOLERANT PATIENTS ONLY. This capsule strength may cause fatal
respiratory depression when ingested or administered to patients who are not
previously exposed to opioids.
Care should be taken in the prescribing of this capsule
strength. Patients should be instructed against use by individuals other than
the patient for whom it was prescribed, as such inappropriate use may have
severe medical consequences, including death.
Misuse, Abuse and Diversion of Opioids
KADIAN® contains morphine an opioid
agonist and a Schedule II controlled substance. Opioid agonists have the
potential for being abused and are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion.
Morphine can be abused in a manner similar to other opioid agonists, legal or
illicit. This should be considered when prescribing or dispensing KADIAN® in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse, or diversion.
Abuse of KADIAN® by crushing, chewing, snorting or
injecting the dissolved product will result in the 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.
Interactions with Alcohol and Drugs of
Abuse
KADIAN® may be expected to have additive
effects when used in conjunction with alcohol, other opioids, or illicit drugs
that cause central nervous system depression because respiratory depression,
hypotension, and profound sedation or coma may result.
Impaired Respiration
Respiratory depression is the chief hazard of all morphine
preparations. Respiratory depression occurs more frequently in elderly and
debilitated patients, and those suffering from conditions accompanied by
hypoxia, hypercapnia, or upper airway obstruction (when even moderate
therapeutic doses may significantly decrease pulmonary ventilation).
KADIAN® should be used with extreme caution in
patients with chronic obstructive pulmonary disease or cor pulmonale, and in
patients having a substantially decreased respiratory reserve (e.g. severe
kyphoscoliosis), hypoxia, hypercapnia, or pre-existing respiratory depression.
In such patients, even usual therapeutic doses of morphine may increase airway
resistance and decrease respiratory drive to the point of apnea. In these
patients, alternative non-opioid analgesics should be considered, and opioids
should be employed only under careful medical supervision at the lowest
effective dose.
Head Injury and Increased Intracranial
Pressure
The respiratory depressant effects of morphine with carbon
dioxide retention and secondary elevation of cerebrospinal fluid pressure may be
markedly exaggerated in the presence of head injury, other intracranial lesions,
or a pre-existing increase in intracranial pressure. KADIAN® produces effects which may obscure neurologic signs of
further increases in pressure in patients with head injuries. Morphine should
only be administered under such circumstances when considered essential and then
with extreme care.
Hypotensive Effect
KADIAN® may cause severe hypotension.
There is an added risk to individuals whose ability to maintain blood pressure
has already been compromised by a reduced blood volume, or a concurrent
administration of drugs such as phenothiazines or general anesthetics. (See also
PRECAUTIONS-Drug
Interactions.) KADIAN® may produce orthostatic
hypotension and syncope in ambulatory patients.
KADIAN®, like all opioid analgesics, should be
administered with caution to patients in circulatory shock, as vasodilation
produced by the drug may further reduce 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
KADIAN® should not be given to patients
with gastrointestinal obstruction, particularly paralytic ileus, as there is a
risk of the product remaining in the stomach for an extended period and the
subsequent release of a bolus of morphine when normal gut motility is restored.
As with other solid morphine formulations diarrhea may reduce morphine
absorption.
Other
Although extremely rare, cases of anaphylaxis have been reported.
PRECAUTIONS
General
KADIAN® is intended for use in patients
who require continuous, around-the-clock opioid analgesia for an extended period
of time. As with any potent opioid, it is critical to adjust the dosing regimen
for KADIAN® for each patient, taking into account the
patient's prior analgesic treatment experience. Although it is clearly
impossible to enumerate every consideration that is important to the selection
of the initial dose of KADIAN®, attention should be given
to the points under DOSAGE AND
ADMINISTRATION.
Opioid analgesics have a narrow therapeutic index in certain patient
populations, especially when combined with CNS depressant drugs, and should be
reserved for cases where the benefits of opioid analgesia outweigh the known
risks of respiratory depression, altered mental state, and postural
hypotension.
Selection of patients for treatment with KADIAN®
should be governed by the same principles that apply to the use of any potent
opioid analgesics. Specifically, the increased risks associated with its use in
the following populations should be considered: the elderly or debilitated and
those with severe impairment of hepatic, pulmonary, or renal function;
hypothyroidism; adrenocortical insufficiency (e.g., Addison's Disease); CNS
depression or coma; toxic psychosis; prostatic hypertrophy, or urethral
stricture; acute alcoholism; delirium tremens; kyphoscoliosis, 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 disorders.
Cordotomy
Patients taking KADIAN® who are scheduled
for cordotomy or other interruption of pain transmission pathways should have
KADIAN® ceased 24 hours prior to the procedure and the
pain controlled by parenteral 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.
Tolerance and Physical Dependence
Tolerance is the need for increasing doses of opioids to maintain
a defined effect such as analgesia (in the absence of disease progression or
other external factors). Physical dependence is manifested by withdrawal
symptoms after abrupt discontinuation of a drug or upon administration of an
antagonist. Physical dependence and tolerance are not unusual during chronic
opioid therapy.
The opioid abstinence or withdrawal syndrome is characterized by some or all
of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration,
chills, myalgia, and mydriasis. Other symptoms also may develop, including:
irritability, anxiety, backache, joint pain, weakness, abdominal cramps,
insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure,
respiratory rate, or heart rate.
In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION:
Cessation of Therapy).
Special Risk Groups
KADIAN® should be administered with
caution, and in reduced dosages in elderly or debilitated patients; patients
with severe renal or hepatic insufficiency; patients with Addison's disease;
myxedema; hypothyroidism; prostatic hypertrophy or urethral stricture.
Caution should also be exercised in the administration of KADIAN® to patients with CNS depression, toxic psychosis, acute
alcoholism and delirium tremens, and convulsive disorders.
Driving and Operating Machinery
KADIAN® may impair the mental and/or
physical abilities needed to perform potentially hazardous activities such as
driving a car or operating machinery. Patients must be cautioned accordingly.
Patients should also be warned about the potential combined effects of
KADIAN® with other CNS depressants, including other
opioids, phenothiazines, sedative/hypnotics and alcohol (see Drug Interactions).
Information for Patients
If clinically advisable, patients receiving KADIAN®, or their caregivers should be given the following
information by the physician, nurse, or pharmacist:
- Patients should be advised that KADIAN® contains
morphine and should be taken only as directed.
- Patients should be advised that KADIAN® capsules
should be swallowed whole (not chewed, crushed, or dissolved). Alternately,
KADIAN® capsules may be opened 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.
- 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 individuals (including
children) other than the patient for whom it was originally prescribed, as such
unsupervised use may have severe, even fatal, consequences.
- Patients should be advised that the dose of KADIAN®
should not be adjusted without consulting the prescribing health care provider.
- Patients 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 medication.
- Patients should be advised that KADIAN® may impair
mental and/or physical ability required for the performance of potentially
hazardous tasks (e.g., driving, operating machinery). Patients started on
KADIAN® or whose dose has been changed should refrain
from dangerous activity until it is established that they are not adversely
affected.
- Patients 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 healthcare provider because dangerous
additive effects may occur resulting in serious injury or death.
- Women of childbearing potential who become or are planning to become
pregnant, should consult their prescribing healthcare provider prior to
initiating or continuing therapy with KADIAN®.
- Patients should be advised that if they have been receiving treatment with
KADIAN® for more than a few weeks and cessation of
therapy is indicated, it may be appropriate to taper the KADIAN® dose, rather than abruptly discontinue it, due to the risk of
precipitating withdrawal symptoms. Their prescribing healthcare provider should
provide a dose schedule to accomplish a gradual discontinuation of the
medication.
- Patients should be advised that KADIAN® is a
potential drug of abuse. They should protect it from theft, and it should never
be given to anyone other than the individual for whom it was prescribed.
- Patients should be advised that severe constipation could occur as a result
of taking KADIAN® and appropriate laxatives, stool
softeners and other appropriate treatments should be initiated from the
beginning of opioid therapy.
- Patients should be instructed to keep KADIAN® in a
secure place out of the reach of children. When KADIAN®
is no longer needed, the unused capsules should 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 coma. When such combined therapy is contemplated, the initial dose of one or
both agents should be reduced by at least 50%.
Muscle Relaxants: KADIAN® may enhance the
neuromuscular blocking action of skeletal relaxants and produce an increased
degree of respiratory depression.
Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics
(i.e., pentazocine, nalbuphine, and butorphanol) should be administered with
caution to a patient who has received or is receiving a course of therapy with a
pure opioid agonist analgesic such as KADIAN®. In this
situation, mixed agonist/antagonist analgesics may reduce the analgesic effect
of KADIAN® and/or may precipitate withdrawal symptoms in
these patients.
Monoamine 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 coma. KADIAN®
should not be used in patients taking MAOIs or within 14 days of stopping such
treatment.
Cimetidine: There is an isolated report of confusion and severe respiratory
depression when a hemodialysis patient was concurrently administered morphine
and cimetidine.
Diuretics: Morphine can reduce the efficacy of diuretics by inducing the
release of antidiuretic hormone. Morphine may also lead to acute retention of
urine by causing spasm of the sphincter of the bladder, particularly in men with
prostatism.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Long-term studies in animals to evaluate the carcinogenic
potential of morphine have not been conducted. There are no reports of
carcinogenic effects in humans. In vitro studies have
reported that morphine is non-mutagenic in the Ames test with Salmonella, and induces chromosomal aberrations in human
leukocytes and lethal mutation induction in Drosophila.
Morphine was found to be mutagenic in vitro in
human T-cells, increasing the DNA fragmentation. In vivo,
morphine was mutagenic in the mouse micronucleus test and induced
chromosomal aberrations in spermatids and murine lymphocytes. Chronic opioid
abusers (e.g., heroin abusers) and their offspring display higher rates of
chromosomal damage. However, the rates of chromosomal abnormalities were similar
in nonexposed individuals and in heroin users enrolled in long term opioid
maintenance programs.
Pregnancy
Teratogenic Effects
(Pregnancy Category C)
Teratogenic effects of morphine have been reported in the animal literature.
High parental doses during the second trimester 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
Morphine given subcutaneously, at non-maternally toxic doses, to
rats during the third trimester with approximately 0.15-fold the MRHD caused
reversible reductions in brain and spinal cord volume, and testes size and body
weight in the offspring, and decreased fertility in female offspring. The
offspring of rats and hamsters treated orally or intraperitoneally throughout
pregnancy with 0.04- to 0.3-fold the MRHD of morphine have demonstrated delayed
growth, motor and sexual maturation and decreased male fertility. Chronic
morphine exposure of fetal animals resulted in mild withdrawal, altered reflex
and motor skill development, and altered responsiveness to morphine that
persisted into adulthood.
There are no well-controlled studies of chronic in utero
exposure to morphine sulfate in human subjects. However, uncontrolled
retrospective studies of human neonates chronically exposed to other opioids
in utero, demonstrated reduced brain volume which
normalized over the first month of life. Infants born to opioid-abusing mothers
are more often small for gestational age, have a decreased ventilatory response
to CO2 and increased risk of sudden infant death
syndrome. KADIAN® should only be used during pregnancy
if the need for strong opioid analgesia justifies the potential risk to the
fetus.
Labor and Delivery
KADIAN® is not recommended for use in
women during and immediately prior to labor, where shorter acting analgesics or
other analgesic techniques are more appropriate. Occasionally, opioid
analgesics may prolong labor through actions which temporarily reduce the
strength, duration and frequency of uterine contractions. However, this effect
is not consistent and may be offset by an increased rate of cervical dilatation
which tends to shorten labor. Neonates whose mothers received opioid analgesics
during labor should be observed closely for signs of respiratory depression. A
specific opioid antagonist, such as naloxone or nalmefene, should be 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. The newborn may experience subsequent neonatal withdrawal
syndrome (NWS). Manifestations of NWS include irritability, hyperactivity,
abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight
loss, and failure to gain weight. The onset, duration, and severity of the
disorder differ based on such factors as the addictive drug used, time and
amount of mother’s last dose, and rate of elimination of the drug from the
newborn. Approaches to the treatment of this syndrome have included supportive
care and, when indicated, drugs such as paregoric or phenobarbital.
Nursing Mothers
Low levels of morphine sulfate have been detected in human milk.
Withdrawal symptoms can occur in breast-feeding infants when maternal
administration of morphine sulfate is 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 available is not suitable for the treatment of very young pediatric
patients or those who are not old enough to take capsules safely. The apple
sauce sprinkling method is not an appropriate alternative for these
patients.
Geriatric Use
Clinical studies of KADIAN® did not
include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
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