Included as part of the "PRECAUTIONS" Section
Addiction, Abuse, And Misuse
Morphine sulfate extended-release tablets contain morphine, a Schedule II controlled substance. As an
opioid, morphine sulfate extended-release tablets expose its users to the risks of addiction, abuse, and
misuse. As modified-release products such as morphine sulfate extended-release tablets 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].
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed morphine sulfate extended-release tablets 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 morphine sulfate
extended-release tablets, 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 morphine sulfate
extended-release tablets, but use in such patients necessitates intensive counseling about the risks of
proper use of morphine sulfate extended-release tablets along with intensive monitoring for signs of
addiction, abuse, and misuse.
Abuse or misuse of morphine sulfate extended-release tablets 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 OVERDOSE].
Opioid agonists such as morphine sulfate extended-release tablets are sought by drug abusers and
people with addiction disorders and are subject to criminal diversion. Consider these risks when
prescribing or dispensing morphine sulfate extended-release tablets. 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-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression has been reported with the use of modifiedrelease
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 OVERDOSE]. 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
morphine sulfate extended-release tablets, the risk is greatest during the initiation of therapy or
following a dose increase. Closely monitor patients for respiratory depression when initiating therapy
with morphine sulfate extended-release tablets and following dose increases.
To reduce the risk of respiratory depression, proper dosing and titration of morphine sulfate extendedrelease
tablets are essential [see DOSAGE AND ADMINISTRATION]. Overestimating the morphine sulfate
extended-release tablets 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 morphine sulfate extended-release tablets, especially by
children, can result in respiratory depression and death due to an overdose of morphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of morphine sulfate extended-release tablets 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 With Central Nervous System Depressants
Hypotension, and profound sedation, coma or respiratory depression may result if morphine sulfate
extended-release tablets are used concomitantly with other central nervous system (CNS) depressants
(e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of morphine sulfate extended-release tablets 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 morphine sulfate
extended-release tablets 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 morphine sulfate
extended-release tablets and when morphine sulfate extended-release tablets are given concomitantly
with other drugs that depress respiration [see Life-Threatening Respiratory Depression].
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 morphine
sulfate extended-release tablets, as in these patients, even usual therapeutic doses of morphine sulfate
extended-release tablets may decrease respiratory drive to the point of apnea [see Life-Threatening Respiratory Depression]. Consider the use of alternative non-opioid analgesics in these patients if possible.
Morphine sulfate extended-release tablets 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
morphine sulfate extended-release tablets. In patients with circulatory shock, morphine sulfate
extended-release tablets may cause vasodilation that can further reduce cardiac output and blood
pressure. Avoid the use of morphine sulfate extended-release tablets in patients with circulatory shock.
Use In Patients With Head Injury Or Increased Intracranial Pressure
Monitor patients taking morphine sulfate extended-release tablets 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
morphine sulfate extended-release tablets. Morphine sulfate extended-release tablets 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 morphine sulfate extended-release tablets in patients with impaired consciousness or
Use In Patients With Gastrointestinal Conditions
Morphine sulfate extended-release tablets are contraindicated in patients with paralytic ileus. Avoid the
use of morphine sulfate extended-release tablets in patients with other GI obstruction.
The morphine in morphine sulfate extended-release tablets 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 Patients With Convulsive Or Seizure Disorders
The morphine in morphine sulfate extended-release tablets 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 morphine sulfate extendedrelease
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, morphine sulfate extended-release tablets. In these patients, mixed
agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate
When discontinuing morphine sulfate extended-release tablets, gradually taper the dose [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue morphine sulfate extended-release tablets.
Driving And Operating Machinery
Morphine sulfate extended-release tablets 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 morphine sulfate extendedrelease
tablets and know how they will react to the medication.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Addiction, Abuse, And Misuse
Inform patients that the use of morphine sulfate extended-release tablets, even when taken as
recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death [see WARNINGS AND PRECAUTIONS]. Instruct patients not to share morphine sulfate extended-release tablets
with others and to take steps to protect morphine sulfate extended-release tablets from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk
is greatest when starting morphine sulfate extended-release tablets or when the dose is increased, and
that it can occur even at recommended doses [see WARNINGS AND PRECAUTIONS]. Advise patients how
to recognize respiratory depression and to seek medical attention if breathing difficulties develop.
Inform patients that accidental ingestion, especially in children, may result in respiratory depression or
death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store morphine sulfate
extended-release tablets securely and to dispose of unused morphine sulfate extended-release tablets by
flushing the tablets down the toilet.
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that prolonged use of morphine sulfate extendedrelease
tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening
if not recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions With Alcohol And Other CNS Depressants
Inform patients that potentially serious additive effects may occur if morphine sulfate extended-release
tablets are used with alcohol or other CNS depressants, and not to use such drugs unless supervised by
a health care provider.
Important Administration Instructions
Instruct patients how to properly take morphine sulfate extended-release tablets, including the
- Swallowing morphine sulfate extended-release tablets whole
- Not crushing, chewing, or dissolving the tablets
- Using morphine sulfate extended-release tablets exactly as prescribed to reduce the risk of lifethreatening
adverse reactions (e.g., respiratory depression)
- Not discontinuing morphine sulfate extended-release tablets without first discussing the need for a
tapering regimen with the prescriber
Inform patients that morphine sulfate extended-release tablets may cause orthostatic hypotension and
syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk
of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or
Driving Or Operating Heavy Machinery
Inform patients that morphine sulfate extended-release tablets may impair the ability to perform
potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not
to perform such tasks until they know how they will react to the medication.
Advise patients of the potential for severe constipation, including management instructions and when to
seek medical attention.
Inform patients that anaphylaxis has been reported with ingredients contained in morphine sulfate
extended-release tablets. Advise patients how to recognize such a reaction and when to seek medical
Advise female patients that morphine sulfate extended-release tablets can cause fetal harm and to inform
the prescriber if they are pregnant or plan to become pregnant.
Healthcare professionals can telephone Rhodes Pharmaceuticals L.P. (1-888-827-0616) for
information on this product.
Disposal Of Unused Morphine Sulfate Extended-Release Tablets
Advise patients to flush the unused tablets down the toilet when morphine sulfate extended-release
tablets are no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Studies in animals to evaluate the carcinogenic potential of morphine have not been
No formal studies to assess the mutagenic potential of morphine have been conducted. In
the published literature, morphine was found to be mutagenic in vitro increasing DNA fragmentation in
human T-cells. Morphine was reported to be mutagenic in the in vivo mouse micronucleus assay and
positive for the induction of chromosomal aberrations in mouse spermatids and murine lymphocytes.
Mechanistic studies suggest that the in vivo clastogenic effects reported with morphine in mice may be
related to increases in glucocorticoid levels produced by morphine in this species. In contrast to the
above positive findings, in vitro studies in the literature have also shown that morphine did not induce
chromosomal aberrations in human leukocytes or translocations or lethal mutations in Drosophila.
Impairment Of Fertility
No formal nonclinical studies to assess the potential of morphine to impair
fertility have been conducted. Several nonclinical studies from the literature have demonstrated adverse
effects on male fertility in the rat from exposure to morphine. One study in which male rats were
administered morphine sulfate subcutaneously prior to mating (up to 30 mg/kg twice daily) and during
mating (20 mg/kg twice daily) with untreated females, a number of adverse reproductive effects
including reduction in total pregnancies, higher incidence of pseudopregnancies, and reduction in
implantation sites were seen. Studies from the literature have also reported changes in hormonal levels
(i.e., testosterone, luteinizing hormone, serum corticosterone) following treatment with morphine.
These changes may be associated with the reported effects on fertility in the rat.
Use In Specific Populations
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].
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Morphine sulfate extendedrelease
tablets should be used during pregnancy only if the potential benefit justifies the potential risk to
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.
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. Morphine sulfate
extended-release tablets are 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.
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
Because of the potential for adverse reactions in nursing infants from morphine sulfate extendedrelease
tablets, a decision should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
The safety and effectiveness in pediatric patients below the age of 18 have not been established.
The pharmacokinetics of morphine sulfate extended-release tablets have not been studied in elderly
patients. Clinical studies of morphine sulfate extended-release tablets 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.