WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse
MS CONTIN contains morphine, a Schedule
II controlled substance. As an opioid, MS CONTIN exposes its users
to the risks of addiction, abuse, and misuse. As modified-release
products such as MS CONTIN deliver the opioid over an extended period
of time, there is a greater risk for overdose and death due to the
larger amount of morphine present [see Drug Abuse and Dependence
(9)].
Although the risk of
addiction in any individual is unknown, it can occur in patients appropriately
prescribed MS CONTIN and in those who obtain the drug illicitly. Addiction
can occur at recommended doses and if the drug is misused or abused.
Assess each
patient’s risk for opioid addiction, abuse, or misuse prior to prescribing
MS CONTIN, and monitor all patients receiving opioids for development
of these behaviors or conditions. Risks are increased in patients
with a personal or family history of substance abuse (including drug
or alcohol abuse or addiction) or mental illness (e.g., major depression).
The potential for these risks should not, however, prevent the proper
management of pain in any given patient. Patients at increased risk
may be prescribed modified-release opioid formulations such as MS
CONTIN, but use in such patients necessitates intensive counseling
about the risks of proper use of MS CONTIN along with intensive monitoring
for signs of addiction, abuse, and misuse.
Abuse or misuse of MS
CONTIN by crushing, chewing, snorting, or injecting the dissolved
product will result in the uncontrolled delivery of morphine and can
result in overdose and death [see Overdosage ].
Opioid agonists
such as MS CONTIN are sought by drug abusers and people with addiction
disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing MS CONTIN. Strategies to reduce these
risks include prescribing the drug in the smallest appropriate quantity
and advising the patient on the proper disposal of unused drug [see Patient Counseling Information]. Contact local state professional licensing board or
state controlled substances authority for information on how to prevent
and detect abuse or diversion of this product.
Life-ThreateningRespiratory Depression
Serious, life-threatening,
or fatal respiratory depression has been reported with the use of
modified-release opioids, even when used as recommended. Respiratory
depression from opioid use, if not immediately recognized and treated,
may lead to respiratory arrest and death. Management of respiratory
depression may include close observation, supportive measures, and
use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ]. Carbon
dioxide (CO2) retention from opioid-induced
respiratory depression can exacerbate the sedating effects of opioids.
While serious,
life-threatening, or fatal respiratory depression can occur at any
time during the use of MS CONTIN, the risk is greatest during the
initiation of therapy or following a dose increase. Closely monitor
patients for respiratory depression when initiating therapy with MS
CONTIN and following dose increases.
To reduce the risk of
respiratory depression, proper dosing and titration of MS CONTIN are
essential [see Dosage and Administration (2)]. Overestimating the MS CONTIN
dose when converting patients from another opioid product can result
in a fatal overdose with the first dose.
Accidental ingestion
of even one dose of MS CONTIN, especially by children, can result
in respiratory depression and death due to an overdose of morphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of MS CONTIN during pregnancy
can result in withdrawal signs in the neonate. Neonatal opioid withdrawal
syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening
if not recognized and treated, and requires management according to
protocols developed by neonatology experts. If opioid use is required
for a prolonged period in a pregnant woman, advise the patient of
the risk of neonatal opioid withdrawal syndrome and ensure that appropriate
treatment will be available.
Neonatal opioid withdrawal
syndrome presents as irritability, hyperactivity and abnormal sleep
pattern, high pitched cry, tremor, vomiting, diarrhea and failure
to gain weight. The onset, duration, and severity of neonatal opioid
withdrawal syndrome vary based on the specific opioid used, duration
of use, timing and amount of last maternal use, and rate of elimination
of the drug by the newborn.
Interactions withCentral Nervous System Depressants
Hypotension, and profound sedation, coma
or respiratory depression may result if MS CONTIN is used concomitantly
with other central nervous system (CNS) depressants (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of MS CONTIN in a patient taking a CNS depressant,
assess the duration of use of the CNS depressant and the patient’s
response, including the degree of tolerance that has developed to
CNS depression. Additionally, evaluate the patient’s use of alcohol
and/or illicit drugs that cause CNS depression. If the decision to
begin MS CONTIN is made, start with the lowest possible dose, 15 mg
every 12 hours, monitor patients for signs of sedation and respiratory
depression, and consider using a lower dose of the concomitant CNS
depressant [see Drug Interactions ].
Use in Elderly, Cachectic, and Debilitated Patients
Life-threatening respiratory
depression is more likely to occur in elderly, cachectic, or debilitated
patients as they may have altered pharmacokinetics or altered clearance
compared to younger, healthier patients. Monitor such patients closely,
particularly when initiating and titrating MS CONTIN and when MS CONTIN
is given concomitantly with other drugs that depress respiration [see Warnings and Precautions].
Use in Patients with Chronic Pulmonary Disease
Monitor patients with significant
chronic obstructive pulmonary disease or cor pulmonale, and patients
having a substantially decreased respiratory reserve, hypoxia, hypercapnia,
or pre-existing respiratory depression for respiratory depression,
particularly when initiating therapy and titrating with MS CONTIN,
as in these patients, even usual therapeutic doses of MS CONTIN may
decrease respiratory drive to the point of apnea [see Warnings
and Precautions ].
Consider the use of alternative non-opioid analgesics in these patients
if possible.
Hypotensive Effects
MS
CONTIN may cause severe hypotension including orthostatic hypotension
and syncope in ambulatory patients. There is an increased risk in
patients whose ability to maintain blood pressure has already been
compromised by a reduced blood volume or concurrent administration
of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions]. Monitor these patients for signs of hypotension after initiating
or titrating the dose of MS CONTIN. In patients with circulatory shock,
MS CONTIN may cause vasodilation that can further reduce cardiac output
and blood pressure. Avoid the use of MS CONTIN in patients with circulatory
shock.
Use in Patientswith Head Injury or Increased Intracranial Pressure
Monitor patients taking MS CONTIN who may be
susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure
or brain tumors) for signs of sedation and respiratory depression,
particularly when initiating therapy with MS CONTIN. MS CONTIN may
reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may
also obscure the clinical course in a patient with a head injury.
Avoid the use of MS CONTIN in patients with
impaired consciousness or coma.
Use in Patientswith Gastrointestinal Conditions
MS CONTIN is contraindicated in patients with paralytic ileus. Avoid
the use of MS CONTIN in patients with other GI obstruction.
The morphine in MS CONTIN may cause spasm
of the sphincter of Oddi. Monitor patients with biliary tract disease,
including acute pancreatitis, for worsening symptoms. Opioids may
cause increases in the serum amylase.
Use in Patientswith Convulsive or Seizure Disorders
The morphine in MS CONTIN
may aggravate convulsions in patients with convulsive disorders, and
may induce or aggravate seizures in some clinical settings. Monitor
patients with a history of seizure disorders for worsened seizure
control during MS CONTIN therapy.
Avoidance of Withdrawal
Avoid the use of mixed agonist/antagonist
(i.e., pentazocine, nalbuphine, and butorphanol) or partial agonist
(buprenorphine) analgesics in patients who have received or are receiving
a course of therapy with a full opioid agonist analgesic, including
MS CONTIN. In these patients, mixed agonists/antagonist and partial
agonist analgesics may reduce the analgesic effect and/or may precipitate
withdrawal symptoms.
When discontinuing MS CONTIN, gradually
taper the dose [see Dosage and Administration ]. Do not abruptly discontinue
MS CONTIN.
Driving and OperatingMachinery
MS CONTIN may impair
the mental or physical abilities needed to perform potentially hazardous
activities such as driving a car or operating machinery. Warn patients
not to drive or operate dangerous machinery unless they are tolerant
to the effects of MS CONTIN and know how they will react to the medication.
USE IN SPECIFIC POPULATIONS
Pregnancy
Clinical Considerations
Fetal/neonatal adverse
reactions
Prolonged use of opioid analgesics
during pregnancy for medical or nonmedical purposes can result in
physical dependence in the neonate and neonatal opioid withdrawal
syndrome shortly after birth. Observe newborns for symptoms of neonatal
opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability,
tremor, rigidity, and seizures, and manage accordingly [see
Warnings and Precautions].
Teratogenic Effects
-Pregnancy Category C
There are no adequate and well-controlled studies in
pregnant women. MS CONTIN should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
In humans, the frequency of congenital
anomalies has been reported to be no greater than expected among the
children of 70 women who were treated with morphine during the first
four months of pregnancy or in 448 women treated with morphine anytime
during pregnancy. Furthermore, no malformations were observed in
the infant of a woman who attempted suicide by taking an overdose
of morphine and other medication during the first trimester of pregnancy.
Several literature reports indicate that
morphine administered subcutaneously during the early gestational
period in mice and hamsters produced neurological, soft tissue and
skeletal abnormalities. With one exception, the effects that have
been reported were following doses that were maternally toxic and
the abnormalities noted were characteristic of those observed when
maternal toxicity is present. In one study, following subcutaneous
infusion of doses greater than or equal to 0.15 mg/kg to mice, exencephaly,
hydronephrosis, intestinal hemorrhage, split supraoccipital, malformed
sternebrae, and malformed xiphoid were noted in the absence of maternal
toxicity. In the hamster, morphine sulfate given subcutaneously on
gestation day 8 produced exencephaly and cranioschisis. In rats treated
with subcutaneous infusions of morphine during the period of organogenesis,
no teratogenicity was observed. No maternal toxicity was observed
in this study, however, increased mortality and growth retardation
were seen in the offspring. In two studies performed in the rabbit,
no evidence of teratogenicity was reported at subcutaneous doses up
to 100 mg/kg.
Non-Teratogenic Effects
Infants born to mothers who have taken opioids chronically
may exhibit neonatal withdrawal syndrome [see Warnings and
Precautions], reversible
reduction in brain volume, small size, decreased ventilatory response
to CO2 and increased risk of sudden infant
death syndrome. Morphine sulfate should be used by a pregnant woman
only if the need for opioid analgesia clearly outweighs the potential
risks to the fetus.
Controlled
studies of chronic in utero morphine exposure in
pregnant women have not been conducted. Published literature has
reported that exposure to morphine during pregnancy in animals is
associated with reduction in growth and a host of behavioral abnormalities
in the offspring. Morphine treatment during gestational periods of
organogenesis in rats, hamsters, guinea pigs and rabbits resulted
in the following treatment-related embryotoxicity and neonatal toxicity
in one or more studies: decreased litter size, embryo-fetal viability,
fetal and neonatal body weights, absolute brain and cerebellar weights,
delayed motor and sexual maturation, and increased neonatal mortality,
cyanosis and hypothermia. Decreased fertility in female offspring,
and decreased plasma and testicular levels of luteinizing hormone
and testosterone, decreased testes weights, seminiferous tubule shrinkage,
germinal cell aplasia, and decreased spermatogenesis in male offspring
were also observed. Decreased litter size and viability were observed
in the offspring of male rats administered morphine (25 mg/kg, IP)
for 1 day prior to mating. Behavioral abnormalities resulting from
chronic morphine exposure of fetal animals included altered reflex
and motor skill development, mild withdrawal, and altered responsiveness
to morphine persisting into adulthood.
Labor and Delivery
Opioids
cross the placenta and may produce respiratory depression in neonates.
MS CONTIN is not for use in women during and immediately prior to
labor, when shorter acting analgesics or other analgesic techniques
are more appropriate. Opioid analgesics can prolong labor through
actions that 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.
Nursing Mothers
Morphine is excreted in
breast milk, with a milk to plasma morphine AUC ratio of approximately
2.5:1. The amount of morphine received by the infant varies depending
on the maternal plasma concentration, the amount of milk ingested
by the infant, and the extent of first pass metabolism.
Withdrawal signs can occur in breast-feeding
infants when maternal administration of morphine is stopped.
Because of the potential for adverse reactions
in nursing infants from MS CONTIN, 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
and effectiveness in pediatric patients below the age of 18 have not
been established.
Geriatric Use
The pharmacokinetics
of MS CONTIN have not been studied in elderly patients. Clinical
studies of MS CONTIN did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from
younger subjects. 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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