Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
MORPHABOND ER contains morphine, a Schedule II controlled
substance. As an opioid, MORPHABOND ER exposes its users to the risks of
addiction, abuse, and misuse. Because extended-release products such as
MORPHABOND ER 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 MORPHABOND ER.
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 MORPHABOND ER, and monitor all patients
receiving MORPHABOND ER for development of these behaviors and 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 opioids such as MORPHABOND ER, but use in such patients
necessitates intensive counseling about the risks of proper use of MORPHABOND
ER along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of MORPHABOND ER 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].
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing MORPHABOND ER. Strategies to reduce these risks
include prescribing the drug in the smallest appropriate quantity and advising
the patient on the proper storage and disposal of unused drug [see PATIENT 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 opioids, even when used as
recommended. Respiratory depression, 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 MORPHABOND ER, the risk is
greatest during the initiation of therapy or following a dosage increase.
Monitor patients closely for respiratory depression, especially within the
first 24-72 hours of initiating therapy with and following dosage increases of
To reduce the risk of respiratory depression, proper
dosing and titration of MORPHABOND ER are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the MORPHABOND ER dosage when converting
patients from another opioid product can result in a fatal overdose with the
Accidental ingestion of even one dose of MORPHABOND ER,
especially by children, can result in respiratory depression and death due to
an overdose of morphine.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of MORPHABOND ER during pregnancy can
result in withdrawal 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. Observe newborns for signs of neonatal opioid
withdrawal syndrome and manage accordingly. Advise pregnant women using opioids
for a prolonged period of the risk of neonatal opioid withdrawal syndrome and
ensure that appropriate treatment will be available [see Use In Specific
Populations, PATIENT INFORMATION].
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of MORPHABOND ER with benzodiazepines
or other CNS system depressants (e.g., non-benzodiazepine sedatives/hypnotics,
tranquilizers, muscle relaxants, general anesthetics, anxiolytics,
antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant
prescribing of these drugs for use in patients for whom alternative treatment
options are inadequate.
Observational studies have demonstrated that concomitant
use of opioid analgesics and benzodiazepines increases the risk of drug-related
mortality compared to use of opioid analgesics alone. Because of similar
pharmacological properties, it is reasonable to expect similar risk with the
concomitant use of other CNS depressant drugs with opioid analgesics [see DRUG
If the decision is made to prescribe a benzodiazepine or
other CNS depressant concomitantly with an opioid analgesic, prescribe the
lowest effective dosages and minimum durations of concomitant use. In patients
already receiving an opioid analgesic, prescribe a lower initial dose of the
benzodiazepine or other CNS depressant than indicated in the absence of an
opioid, and titrate based on clinical response. If an opioid analgesic is
initiated in a patient already taking a benzodiazepine or other CNS depressant,
prescribe a lower initial dose of the opioid analgesic, and titrate based on
clinical response. Follow patients closely for signs and symptoms of respiratory
depression and sedation.
Advise both patients and caregivers about the risks of
respiratory depression and sedation when MORPHABOND ER is used with
benzodiazepines or other CNS depressants (including alcohol and illicit drugs).
Advise patients not to drive or operate heavy machinery until the effects of concomitant
use of the benzodiazepine or other CNS depressant have been determined. Screen patients
for risk of substance use disorders, including opioid abuse and misuse, and
warn them of the risk for overdose and death associated with the use of
additional CNS depressants including alcohol and illicit drugs [see DRUG
INTERACTIONS and PATIENT INFORMATION].
Life -Threatening Respiratory Depression In Patients With
Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of MORPHABOND ER in patients with acute or severe
bronchial asthma in an unmonitored setting or in the absence of resuscitative
equipment is contraindicated.
Patients With Chronic Pulmonary Disease
MORPHABOND ER-treated patients with significant chronic
obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased
respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory
depression are at increased risk of decreased respiratory drive including
apnea, even at recommended dosages of MORPHABOND ER [see Life-Threatening Respiratory Depression].
Elderly, Cachectic, Or 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 [see
Life-Threatening Respiratory Depression].
Monitor such patients closely, particularly when
initiating and titrating MORPHABOND ER and when MORPHABOND ER is given
concomitantly with other drugs that depress respiration [see Life-Threatening Respiratory Depression and Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants]. Alternatively, consider the use of non-opioid analgesics in these
Interaction With Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) may potentiate the
effects of morphine, including respiratory depression, coma, and confusion.
MORPHABOND ER should not be used in patients taking MAOIs or within 14 days of
stopping such treatment.
Cases of adrenal insufficiency have been reported with
opioid use, more often following greater than one month of use. Presentation of
adrenal insufficiency may include non-specific symptoms and signs including
nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing
as soon as possible. If adrenal insufficiency is diagnosed, treat with
physiologic replacement doses of corticosteroids. Wean the patient off of the
opioid to allow adrenal function to recover and continue corticosteroid
treatment until adrenal function recovers. Other opioids may be tried as some
cases reported use of a different opioid without recurrence of adrenal
insufficiency. The information available does not identify any particular
opioids as being more likely to be associated with adrenal insufficiency.
MORPHABOND ER may cause severe hypotension including
orthostatic hypotension and syncope in ambulatory patients. There is 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 dosage of MORPHABOND ER. In patients with
circulatory shock, MORPHABOND ER may cause vasodilation that can further reduce
cardiac output and blood pressure. Avoid the use of MORPHABOND ER in patients
with circulatory shock.
Risks Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness
In patients who may be susceptible to the intracranial
effects of CO2 retention (e.g., those with evidence of increased intracranial
pressure or brain tumors), MORPHABOND ER may reduce respiratory drive, and the
resultant CO2 retention can further increase intracranial pressure. Monitor
such patients for signs of sedation and respiratory depression, particularly
when initiating therapy with MORPHABOND ER.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of MORPHABOND ER in patients with impaired
consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
MORPHABOND ER is contraindicated in patients with known
or suspected gastrointestinal obstruction, including paralytic ileus.
The morphine in MORPHABOND ER may cause spasm of the
sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor
patients with biliary tract disease, including acute pancreatitis, for worsening
Increased Risk Of Seizures In Patients With Seizure
The morphine in MORPHABOND ER may increase the frequency
of seizures in patients with seizure disorders, and may increase the risk of
seizures occurring in other clinical settings associated with seizures. Monitor
patients with a history of seizure disorders for worsened seizure control
during MORPHABOND ER therapy.
Avoid the use of mixed agonist/antagonist (e.g.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g.,
buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic,
including MORPHABOND ER. In these patients, mixed agonists/antagonist and partial
agonist analgesics may reduce the analgesic effect and/or may precipitate
withdrawal symptoms [see DRUG INTERACTIONS].
When discontinuing MORPHABOND ER, gradually taper the
dosage [see DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue
MORPHABOND ER [see Drug Abuse And Dependence].
Risks Of Driving And Operating Machinery
MORPHABOND ER 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 MORPHABOND ER and know how they will
react to the medication [see PATIENT INFORMATION].
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
MORPHABOND ER, even when taken as recommended, can result in addiction, abuse,
and misuse, which can lead to overdose and death [see WARNINGS AND
Instruct patients not to share MORPHABOND ER with others and to take steps to
protect MORPHABOND ER from theft or misuse.
Inform patients of the risk of
life-threatening respiratory depression, including information that the risk is
greatest when starting MORPHABOND ER or when the dosage is increased, and that it
can occur even at recommended dosages [see WARNINGS AND PRECAUTIONS]. Advise patients how to
recognize respiratory depression and to seek medical attention if breathing difficulties
Inform patients that accidental
ingestion, especially by children, may result in respiratory depression or
death [see WARNINGS AND PRECAUTIONS]. Instruct patients to take steps to store MORPHABOND ER
securely and to dispose of unused MORPHABOND ER by flushing the tablets down
Interactions With Benzodiazepines
And Other CNS Depressants
Inform patients and caregivers
that potentially fatal additive effects may occur if MORPHABOND ER is used with
benzodiazepines or other CNS depressants, including alcohol, and not to use
these concomitantly unless supervised by a health care provider [see WARNINGS
AND PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that opioids
could cause a rare but potentially life-threatening condition resulting from
concomitant administration of serotonergic drugs. Warn patients of the symptoms
of serotonin syndrome and to seek medical attention right away if symptoms
develop. Instruct patients to inform their physicians if they are taking, or
plan to take serotonergic medications [see DRUG INTERACTIONS].
Inform patients not to take
MORPHABOND ER while using any drugs that inhibit monoamine oxidase. Patients
should not start MAOIs while taking MORPHABOND ER [see WARNINGS AND
PRECAUTIONS, DRUG INTERACTIONS].
Inform patients that opioids
could cause adrenal insufficiency, a potentially life-threatening condition.
Adrenal insufficiency may present with non-specific symptoms and signs such as nausea,
vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.
Advise patients to seek medical attention if they experience a constellation of
these symptoms [see WARNINGS AND PRECAUTIONS].
[see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]
Instruct patients how to
properly take MORPHABOND ER, including the following:
- Swallowing MORPHABOND ER
tablets whole [see DOSAGE AND ADMINISTRATION]
- Not crushing, chewing, or
dissolving the tablets [see DOSAGE AND ADMINISTRATION]
- Using MORPHABOND ER exactly as
prescribed to reduce the risk of life-threatening adverse reactions (e.g.,
respiratory depression) [see WARNINGS AND PRECAUTIONS]
- Not discontinuing MORPHABOND ER
without first discussing the need for a tapering regimen with the prescriber [see DOSAGE AND ADMINISTRATION]
Inform patients that MORPHABOND
ER 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 lying position) [see WARNINGS AND PRECAUTIONS.]
Inform patients that
anaphylaxis has been reported with ingredients contained in MORPHABOND ER.
Advise patients how to recognize such a reaction and when to seek medical
attention [see CONTRAINDICATIONS, ADVERSE REACTIONS].
Neonatal Opioid Withdrawal
Inform female patients of
reproductive potential that prolonged use of MORPHABOND ER during pregnancy can
result in neonatal opioid withdrawal syndrome, which may be lifethreatening if
not recognized and treated [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Inform female patients of
reproductive potential that MORPHABOND ER can cause fetal harm and to inform
the healthcare provider of a known or suspected pregnancy [see Use In Specific
Advise patients that
breastfeeding is not recommended during treatment with MORPHABOND ER [see Use
In Specific Populations].
Inform patients that chronic
use of opioids may cause reduced fertility. It is not known whether these
effects on fertility are reversible [see Use In Specific Populations].
Driving Or Operating Heavy
Inform patients that MORPHABOND
ER 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 [see WARNINGS
Advise patients of the
potential for severe constipation, including management instructions and when
to seek medical attention [see ADVERSE REACTIONS, CLINICAL
Disposal Of Unused MORPHABOND ER
Advise patients to flush the
unused tablets down the toilet when MORPHABOND ER is no longer needed.
Healthcare professionals can
telephone Daiichi Sankyo, Inc. (1-877-437-7763) for information on this
Impairment Of Fertility
Long-term studies in animals to
evaluate the carcinogenic potential of morphine have not been conducted.
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 and higher incidence of pseudopregnancies at 20
mg/kg/day (3.2 times the HDD) were reported. Studies from the literature have
also reported changes in hormonal levels in male rats (i.e. testosterone,
luteinizing hormone) following treatment with morphine at 10 mg/kg/day or
greater (1.6 times the HDD).
Female rats that were
administered morphine sulfate intraperitoneally prior to mating exhibited prolonged
estrous cycles at 10 mg/kg/day (1.6 times the HDD).
Exposure of adolescent male
rats to morphine has been associated with delayed sexual maturation and
following mating to untreated females, smaller litters, increased pup
mortality, and/or changes in reproductive endocrine status in adult male
offspring have been reported (estimated 5 times the plasma levels at the HDD).
Use In Specific Populations
Prolonged use of opioid analgesics during pregnancy can
cause neonatal opioid withdrawal syndrome [see WARNINGS AND PRECAUTIONS].
There are no available data with MORPHABOND ER in pregnant women to inform a
drug-associated risk for major birth defects and miscarriage. Published studies
with morphine use during pregnancy have not reported a clear association with
morphine and major birth defects [see Human Data]. In published animal reproduction
studies, morphine administered subcutaneously during the early gestational
period produced neural tube defects (i.e., exencephaly and cranioschisis) at 5
and 16 times the human daily dose of 60 mg based on body surface area (HDD) in
hamsters and mice, respectively, lower fetal body weight and increased
incidence of abortion at 0.4 times the HDD in the rabbit, growth retardation at
6 times the HDD in the rat, and axial skeletal fusion and cryptorchidism at 16
times the HDD in the mouse. Administration of morphine sulfate to pregnant rats
during organogenesis and through lactation resulted in cyanosis, hypothermia,
decreased brain weights, pup mortality, decreased pup body weights, and adverse
effects on reproductive tissues at 3-4 times the HDD; and long-term
neurochemical changes in the brain of offspring which correlate with altered
behavioral responses that persist through adulthood at exposures comparable to
and less than the HDD [see Animal Data]. Based on animal data, advise
pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
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. 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. Observe newborns for symptoms of neonatal opioid withdrawal syndrome
and manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor Or Delivery
Opioids cross the placenta and may produce respiratory
depression and psycho-physiologic effects in neonates. An opioid antagonist,
such as naloxone, must be available for reversal of opioid-induced respiratory
depression in the neonate. MORPHABOND ER is not recommended for use in women
during and immediately prior to labor, when shorter acting analgesics or other analgesic
techniques are more appropriate. Opioid analgesics, including MORPHABOND ER, 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. Monitor neonates exposed to opioid analgesics during labor for
signs of excess sedation and respiratory depression.
The results from a population-based prospective cohort,
including 70 women exposed to morphine during the first trimester of pregnancy
and 448 women exposed to morphine at any time during pregnancy, indicate no
increased risk for congenital malformations. However, these studies cannot
definitely establish the absence of any risk because of methodological
limitations, including small sample size and non-randomized study design.
Formal reproductive and developmental toxicology studies
for morphine have not been conducted. Exposure margins for the following
published study reports are based on a human daily dose of 60 mg morphine using
a body surface area comparison (HDD).
Neural tube defects (exencephaly and cranioschisis) were
noted following subcutaneous administration of morphine sulfate (35-322 mg/kg)
on Gestation Day 8 to pregnant hamsters (4.7 to 43.5 times the HDD). A no
adverse effect level was not defined in this study and the findings cannot be
clearly attributed to maternal toxicity. Neural tube defects (exencephaly), axial
skeletal fusions, and cryptorchidism were reported following a single
subcutaneous (SC) injection of morphine sulfate to pregnant mice (100-500
mg/kg) on Gestation Day 8 or 9 at 200 mg/kg or greater (16 times the HDD) and
fetal resorption at 400 mg/kg or higher (32 times the HDD). No adverse effects
were noted following 100 mg/kg morphine in this model (8 times the HDD). In one
study, following continuous subcutaneous infusion of doses greater than or equal
to 2.72 mg/kg to mice (0.2 times the HDD), exencephaly, hydronephrosis,
intestinal hemorrhage, split supraoccipital, malformed sternebrae, and
malformed xiphoid were noted. The effects were reduced with increasing daily
dose; possibly due to rapid induction of tolerance under these infusion
conditions. The clinical significance of this report is not clear.
Decreased fetal weights were observed in pregnant rats
treated with 20 mg/kg/day morphine sulfate (3.2 times the HDD) from Gestation
Day 7 to 9. There was no evidence of malformations despite maternal toxicity
(10% mortality). In a second rat study, decreased fetal weight and increased
incidences of growth retardation were noted at 35 mg/kg/day (5.7 times the HDD)
and there was a reduced number of fetuses at 70 mg/kg/day (11.4 times the HDD)
when pregnant rats were treated with 10, 35, or 70 mg/kg/day morphine sulfate
via continuous infusion from Gestation Day 5 to 20. There was no evidence of
fetal malformations or maternal toxicity.
An increased incidence of abortion was noted in a study
in which pregnant rabbits were treated with 2.5 (0.8 times the HDD) to 10 mg/kg
morphine sulfate via subcutaneous injection from Gestation Day 6 to 10. In a
second study, decreased fetal body weights were reported following treatment of
pregnant rabbits with increasing doses of morphine (10-50 mg/kg/day) during the
pre-mating period and 50 mg/kg/day (16 times the HDD) throughout the gestation
period. No overt malformations were reported in either publication; although
only limited endpoints were evaluated.
In published studies in rats, exposure to morphine during
gestation and/or lactation periods is associated with: decreased pup viability
at 12.5 mg/kg/day or greater (2 times the HDD); decreased pup body weights at
15 mg/kg/day or greater (2.4 times the HDD); decreased litter size, decreased
absolute brain and cerebellar weights, cyanosis, and hypothermia at 20
mg/kg/day (3.2 times the HDD); alteration of behavioral responses (play,
social-interaction) at 1 mg/kg/day or greater (0.2 times the HDD); alteration
of maternal behaviors (e.g., decreased nursing and pup retrievals) in mice at 1
mg/kg or higher (0.08 times the HDD) and rats at 1.5 mg/kg/day or higher (0.2
times the HDD); and a host of behavioral abnormalities in the offspring of
rats, including altered responsiveness to opioids at 4 mg/kg/day (0.7 times the
HDD) or greater.
Fetal and/or postnatal exposure to morphine in mice and
rats has been shown to result in morphological changes in fetal and neonatal
brain and neuronal cell loss, alteration of a number of neurotransmitter and
neuromodulator systems, including opioid and non-opioid systems, and impairment
in various learning and memory tests that appear to persist into adulthood.
These studies were conducted with morphine treatment usually in the range of 4
to 20 mg/kg/day (0.7 to 3.2 times the HDD).
Additionally, delayed sexual maturation and decreased
sexual behaviors in female offspring at 20 mg/kg/day (3.2 times the HDD), 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 at 20
mg/kg/day (3.2 times the HDD). Decreased litter size and viability were
observed in the offspring of male rats that were intraperitoneally administered
morphine sulfate for 1 day prior to mating at 25 mg/kg/day (4.1 times the HDD)
and mated to untreated females. Decreased viability and body weight and/or
movement deficits in both first and second generation offspring were reported
when male mice were treated for 5 days with escalating doses of 120 to 240
mg/kg/day morphine sulfate (9.7 to 19.5 times the HDD) or when female mice
treated with escalating doses of 60 to 240 mg/kg/day (4.9 to 19.5 times the
HDD) followed by a 5-day treatment-free recovery period prior to mating.
Similar multigenerational findings were also seen in female rats pre-gestationally
treated with escalating doses of 10 to 22 mg/kg/day morphine (1.6 to 3.6 times the
Morphine is present in breast milk. Published lactation
studies report variable concentrations of morphine in breast milk with
administration of immediate-release morphine to nursing mothers in the early
postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in
one lactation study. However, there is insufficient information to determine
the effects of morphine on the breastfed infant and the effects of morphine on
milk production. Lactation studies have not been conducted with
extended-release morphine, including MORPHABOND ER. Because of the potential
for serious adverse reactions, including excess sedation and respiratory
depression in a breastfed infant, advise patients that breastfeeding is not recommended
during treatment with MORPHABOND ER.
Monitor infants exposed to MORPHABOND ER through breast
milk for excess sedation and respiratory depression. Withdrawal symptoms can
occur in breastfed infants when maternal administration of morphine is stopped,
or when breastfeeding is stopped.
Females And Males Of Reproductive Potential
Chronic use of opioids may cause reduced fertility in
females and males of reproductive potential. It is not known whether these
effects on fertility are reversible [see ADVERSE REACTIONS, CLINICAL
In published animal studies, morphine administration
adversely effected fertility and reproductive endpoints in male rats and
prolonged estrus cycle in female rats [see Nonclinical Toxicology].
The safety and effectiveness in pediatric patients below
the age of 18 have not been established.
The pharmacokinetics of MORPHABOND ER have not been
studied in elderly patients. Clinical studies of morphine sulfate
extended-release did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects.
Elderly patients (aged 65 years or older) may have
increased sensitivity to morphine. In general, dosage 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.
Respiratory depression is the chief risk for elderly
patients treated with opioids, and has occurred after large initial doses were
administered to patients who were not opioid-tolerant or when opioids were
co-administered with other agents that depress respiration. Titrate the dosage
of MORPHABOND ER slowly in geriatric patients and monitor closely for signs of
central nervous system and respiratory depression [see WARNINGS AND
Morphine is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and
it may be useful to monitor renal function.
Morphine pharmacokinetics have been reported to be
significantly altered in patients with cirrhosis. Start these patients with a
lower than usual dosage of MORPHABOND ER and titrate slowly while monitoring
for signs of respiratory depression, sedation, and hypotension [see CLINICAL
Morphine pharmacokinetics are altered in patients with
renal failure. Start these patients with a lower than usual dosage of
MORPHABOND ER and titrate slowly while monitoring for signs of respiratory
depression, sedation, and hypotension [see CLINICAL PHARMACOLOGY].