Included as part of the PRECAUTIONS section.
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. Because extended-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].
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed MS CONTIN. 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 MS
CONTIN 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 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].
Opioids 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-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 MS CONTIN, 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 and following dosage increases of with MS CONTIN.
To reduce the risk of respiratory depression, proper
dosing and titration of MS CONTIN are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the MS CONTIN dosage 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
Neonatal Opioid Withdrawal Syndrome
Prolonged use of MS CONTIN 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 MS CONTIN with benzodiazepines or
other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics,
anxiolytics, tranquilizers, muscle relaxants, general anesthetics,
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 MS CONTIN 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, PATIENT INFORMATION].
Risk Of Life-Threatening Respiratory Depression In Patients
With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated
The use of MS CONTIN 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
MS CONTIN-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 MS CONTIN [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 MS CONTIN and when MS CONTIN is given concomitantly
with other drugs that depress respiration [see Life-Threatening Respiratory Depression].
Alternatively, consider the use of non-opioid analgesics in these patients.
Interaction With Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) may potentiate the
effects of morphine, including respiratory depression, coma, and confusion. MS
CONTIN 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
MS CONTIN 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 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
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), MS CONTIN 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 MS CONTIN.
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.
Risks Of Use In Patients With Gastrointestinal Conditions
MS CONTIN is contraindicated in patients with known or
suspected gastrointestinal obstruction, including paralytic ileus.
The morphine in MS CONTIN may cause spasm of the
sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor
patients with biliary tract disease, including acute pancreatitis, for
Increased Risk Of Seizures In Patients With Seizure
The morphine in MS CONTIN 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 MS CONTIN therapy.
Avoid the use of mixed agonist/antagonist (e.g.,
pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g.,
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 [see DRUG
When discontinuing MS CONTIN, gradually taper the dosage [see
DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue MS CONTIN [see Drug
Abuse And Dependence].
Risks Of Driving And Operating Machinery
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 [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 MS CONTIN, even when
taken as recommended, can result in addiction, abuse, and misuse, which can
lead to overdose and death [see WARNINGS AND PRECAUTIONS]. Instruct patients
not to share MS CONTIN with others and to take steps to protect MS CONTIN 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 MS CONTIN or when the dosage 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
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 MS CONTIN securely and
to dispose of unused MS CONTIN by flushing the tablets down the toilet.
Interactions With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if MS CONTIN is used with benzodiazepines or other
CNS depressants, including alcohol, and not to use these concomitantly unless
supervised by a healthcare provider [see WARNINGS AND PRECAUTIONS, DRUG
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 MS CONTIN while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking MS CONTIN [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
Important Administration Instructions
Instruct patients how to properly take MS CONTIN,
including the following:
- Swallow MS CONTIN tablets whole [see DOSAGE AND
- Do not crush, chew, or dissolve the tablets [see DOSAGE
- Use MS CONTIN exactly as prescribed to reduce the risk of
life-threatening adverse reactions (e.g., respiratory depression) [see WARNINGS
- Do not discontinue MS CONTIN without first discussing the
need for a tapering regimen with the prescriber [see DOSAGE AND ADMINISTRATION]
Inform patients that MS CONTIN 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 MS CONTIN. Advise patients how to recognize such a
reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE
Neonatal Opioid Withdrawal Syndrome
Inform female patients of reproductive potential that
prolonged use of MS CONTIN during pregnancy can result in neonatal opioid
withdrawal syndrome, which may be life-threatening if not recognized and treated
[see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Inform female patients of reproductive potential that MS
CONTIN can cause fetal harm and to inform their healthcare provider of a known
or suspected pregnancy [see ADVERSE REACTIONS].
Advise patients that breastfeeding is not recommended
during treatment with MS CONTIN [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 [Use In Specific Populations].
Driving Or Operating Heavy Machinery
Inform patients that MS CONTIN 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.
Disposal Of Unused MS CONTIN
Advise patients to flush the unused tablets down the
toilet when MS CONTIN is no longer needed.
Healthcare professionals can telephone Rhodes
Pharmaceuticals L.P.'s Medical Services Department (1-888-827-0616) for information
on this product.
Carcinogenesis, Mutagenesis, 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 may
cause neonatal withdrawal syndrome [see WARNINGS AND PRECAUTIONS]. There
are no available data with MS CONTIN 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%, respectively.
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. MS CONTIN is not recommended for use in pregnant
women during or immediately prior to labor, when use of shorter-acting
analgesics or other analgesic techniques are more appropriate. Opioid
analgesics, including MS CONTIN, can 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 dilation, 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 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 HDD).
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 MS Contin. 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 MS CONTIN.
Monitor infants exposed to MS CONTIN through breast milk
for excess sedation and respiratory depression. Withdrawal symptoms can occur
in breastfed infants when maternal administration of an opioid analgesic is
stopped, or when breast-feeding 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 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.
Elderly patients (aged 65 years or older) may have
increased sensitivity to morphine. In general, use caution when selecting a
dosage for an elderly patient, 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 MS CONTIN
slowly in geriatric patients and monitor closely for signs of central nervous
system and respiratory depression [see WARNINGS AND PRECAUTIONS].
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 MS CONTIN 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 MS CONTIN
and titrate slowly while monitoring for signs of respiratory depression,
sedation, and hypotension [see CLINICAL PHARMACOLOGY].