Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
OPANA ER contains oxymorphone, a Schedule II controlled
substance. As an opioid, OPANA ER exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence]. As modified-release
products such as OPANA 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
Although the risk of addiction in any individual is
unknown, it can occur in patients appropriately prescribed OPANA ER 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 abuse or addiction,
abuse, or misuse prior to prescribing OPANA ER, and monitor all patients
receiving OPANA ER for the development of these behaviors or conditions. Risks
are increased in patients with a personal or family history of substance abuse
(including drug or alcohol addiction or abuse) or mental illness (e.g., major
depression). The potential for these risks should not, however, prevent the
prescribing of OPANA ER for the proper management of pain in any given patient.
Patients at increased risk may be prescribed modified-release opioid
formulations such as OPANA ER, but use in such patients necessitates intensive
counseling about the risks and proper use of OPANA ER along with intensive
monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of OPANA ER by crushing, chewing,
snorting, or injecting the dissolved product will result in the uncontrolled
delivery of the oxymorphone and can result in overdose and death [see
Opioid agonists such as OPANA ER are sought by drug
abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing OPANA ER.
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 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 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 OPANA ER, the risk is
greatest during the initiation of therapy or following a dose increase. Closely
monitor patients for respiratory depression when initiating therapy with OPANA
ER and following dose increases.
To reduce the risk of respiratory depression, proper
dosing and titration of OPANA ER are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the OPANA ER dose when converting patients
from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of OPANA ER,
especially by children, can result in respiratory depression and death due to
an overdose of oxymorphone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of OPANA ER 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
Patients must not consume alcoholic beverages or
prescription or non-prescription products containing alcohol while on OPANA ER
therapy. The co-ingestion of alcohol with OPANA ER may result in increased
plasma levels and a potentially fatal overdose of oxymorphone [see CLINICAL
Hypotension, profound sedation, coma, respiratory
depression, and death may result if OPANA ER is used concomitantly with alcohol
or other central nervous system (CNS) depressants (e.g., sedatives,
anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of OPANA ER 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 or illicit
drugs that cause CNS depression. If the decision to begin OPANA ER is made,
start with OPANA ER 5 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 OPANA
ER and when OPANA ER is 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 OPANA ER, as in these patients, even usual
therapeutic doses of OPANA ER 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.
Use In Patients With Hepatic Impairment
A study of OPANA ER in patients with hepatic disease
indicated greater plasma concentrations than those with normal hepatic function
[see CLINICAL PHARMACOLOGY]. OPANA ER is contraindicated in patients
with moderate or severe hepatic impairment. In patients with mild hepatic
impairment reduce the starting dose to the lowest dose and monitor for signs of
respiratory and central nervous system depression [see DOSAGE AND
OPANA ER 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 OPANA ER. In patients with circulatory
shock, OPANA ER may cause vasodilation that can further reduce cardiac output
and blood pressure. Avoid the use of OPANA ER in patients with circulatory
Use In Patients With Head Injury Or Increased
Monitor patients taking OPANA ER 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 OPANA ER.
OPANA ER 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 OPANA ER in patients
with impaired consciousness or coma.
Difficulty In Swallowing And Risk For Obstruction In Patients
At Risk For A Small Gastrointestinal Lumen
There have been post-marketing reports of difficulty in
swallowing Opana ER tablets. These reports included choking, gagging,
regurgitation and tablets stuck in the throat. Instruct patients not to
pre-soak, lick or otherwise wet Opana ER tablets prior to placing in the mouth,
and to take one tablet at a time with enough water to ensure complete
swallowing immediately after placing in the mouth.
There have been rare post-marketing reports of cases of
intestinal obstruction, some of which have required medical intervention to
remove the tablet. Patients with underlying GI disorders such as esophageal
cancer or colon cancer with a small gastrointestinal lumen are at greater risk
of developing these complications. Consider use of an alternative analgesic in
patients who have difficulty swallowing and patients at risk for underlying GI
disorders resulting in a small gastrointestinal lumen.
Use In Patients With Gastrointestinal Conditions
OPANA ER is contraindicated in patients with paralytic
ileus. Avoid the use of OPANA ER in patients with other GI obstruction.
The oxymorphone in OPANA ER 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
Use In Patients With Convulsive Or Seizure Disorders
The oxymorphone in OPANA ER 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 OPANA ER therapy.
Avoidance Of Withdrawal
Avoid the use of mixed agonist/antagonist (i.e.,
pentazocine, nalbuphine, and butorphanol) and partial agonist (buprenorphine)
analgesics in patients who have received or are receiving a course of therapy
with an opioid agonist analgesic, including OPANA ER. In these patients, mixed
agonists/antagonist and partial agonist analgesics may reduce the analgesic
effect and/or may precipitate withdrawal symptoms.
When discontinuing OPANA ER, gradually taper the dose [see
DOSAGE AND ADMINISTRATION]. Do not abruptly discontinue OPANA ER.
Driving And Operating Machinery
OPANA 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 OPANA ER 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
OPANA ER, even when taken as recommended, can result in addiction, abuse, and
misuse, which can lead to overdose or death [see WARNINGS AND
Instruct patients not to share OPANA ER with others and to take steps to
protect OPANA ER from theft or misuse.
Inform patients of the risk of
life-threatening respiratory depression, including information that the risk is
greatest when starting OPANA ER 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
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 OPANA ER
securely and to dispose of unused OPANA ER by flushing the tablets down the
Neonatal Opioid Withdrawal
Inform female patients of
reproductive potential that prolonged use of OPANA ER during pregnancy can
result in neonatal opioid withdrawal syndrome, which may be life-threatening if
not recognized and treated [see WARNINGS AND PRECAUTIONS].
Interactions with Alcohol and
other CNS Depressants
Instruct patients not to
consume alcoholic beverages, as well as prescription and over-the-counter
products that contain alcohol, during treatment with OPANA ER. The co-ingestion
of alcohol with OPANA ER may result in increased plasma levels and a
potentially fatal overdose of oxymorphone [see WARNINGS AND
Inform patients that
potentially serious additive effects may occur if OPANA ER is 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 OPANA ER,
including the following:
- Swallowing OPANA ER tablets whole
- Not crushing, chewing, or dissolving the tablets
- Occasionally, the inactive ingredients of OPANA ER may be
eliminated as a soft mass in the stool that may resemble the original tablet.
Patients should be informed that the active medication has already been
absorbed by the time the patient sees the soft mass.
- Using OPANA ER exactly as prescribed to reduce the risk
of life-threatening adverse reactions (e.g., respiratory depression)
- Not discontinuing OPANA ER without first discussing the
need for a tapering regimen with the prescriber
- Do not pre-soak, lick or otherwise wet the tablet prior
to placing in the mouth.
- To take each tablet with enough water to ensure complete
swallowing immediately after placing in mouth.
Inform patients that OPANA 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).
Driving or Operating Heavy
Inform patients that OPANA 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.
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 OPANA ER. Advise
patients how to recognize such a reaction and when to seek medical attention.
Advise female patients that
OPANA ER can cause fetal harm and to inform the prescriber if they are pregnant
or plan to become pregnant.
Disposal of Unused OPANA ER
Advise patients to flush the
unused tablets down the toilet when OPANA ER is no longer needed.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies have been completed to evaluate the
carcinogenic potential of oxymorphone in both Sprague-Dawley rats and CD-1
mice. Oxymorphone HCl was administered to Sprague-Dawley rats (2.5, 5, and 10
mg/kg/day in males and 5, 10, and 25 mg/kg/day in females) for 2 years by oral
gavage. The systemic drug exposure (AUC ng•h/mL) at the 10 mg/kg/day in male
rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5-fold the
human exposure at a dose of 260 mg/day. No evidence of carcinogenic potential
was observed in rats. Oxymorphone was administered to CD-1 mice (10, 25, 75 and
150 mg/kg/day) for 2 years by oral gavage. The systemic drug exposure (AUC
ng•h/mL) at the 150 mg/kg/day dose in mice was 14.5-fold (in males) and
17.3-fold (in females) times the human exposure at a dose of 260 mg/day. No
evidence of carcinogenic potential was observed in mice.
Oxymorphone hydrochloride was not mutagenic when tested
in the in vitro bacterial reverse mutation assay (Ames test) at concentrations
of ≤ 5270 μg/plate, or in an in vitro mammalian cell chromosome
aberration assay performed with human peripheral blood lymphocytes at
concentrations ≤ 5000 μg/ml with or without metabolic activation.
Oxymorphone hydrochloride tested positive in both the rat and mouse in vivo micronucleus
assays. An increase in micronucleated polychromatic erythrocytes occurred in
mice given doses ≥ 250 mg/kg and in rats given doses of 20 and 40 mg/kg. A
subsequent study demonstrated that oxymorphone hydrochloride was not aneugenic
in mice following administration of up to 500 mg/kg. Additional studies
indicate that the increased incidence of micronucleated polychromatic
erythrocytes in rats may be secondary to increased body temperature following
oxymorphone administration. Doses associated with increased micronucleated
polychromatic erythrocytes also produce a marked, rapid increase in body
temperature. Pretreatment of animals with sodium salicylate minimized the
increase in body temperature and prevented the increase in micronucleated
polychromatic erythrocytes after administration of 40 mg/kg oxymorphone.
Impairment of Fertility
Oxymorphone hydrochloride did not affect reproductive
function or sperm parameters in male rats at any dose tested ( ≤ 50
mg/kg/day). The highest dose tested is ≤ 6-fold
the human dose of 40 mg every 12 hours, based on body surface area. In female
rats, an increase in the length of the estrus cycle and decrease in the mean
number of viable embryos, implantation sites and corpora lutea were observed at
doses of oxymorphone ≥ 10 mg/kg/day. The dose of oxymorphone associated
with reproductive findings in female rats is 1.2-fold the human dose of 40 mg
every 12 hours based on a body surface area. The dose of oxymorphone that
produced no adverse effects on reproductive findings in female rats is 0.6-fold
the human dose of 40 mg every 12 hours on a body surface area basis.
Use In Specific Populations
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
Teratogenic Effects -Pregnancy
There are no adequate and
well-controlled studies in pregnant women. OPANA ER should be used during
pregnancy only if the potential benefit justifies the potential risk to the
Oxymorphone hydrochloride administration did not cause
malformations at any doses evaluated during developmental toxicity studies in
rats ( ≤ 25 mg/kg/day) or rabbits ( ≤ 50 mg/kg/day). These doses are ≤ 3-fold and ≤ 12-fold the human dose
of 40 mg every 12 hours, based on body surface area. There were no
developmental effects in rats treated with 5 mg/kg/day or rabbits treated with
25 mg/kg/day. Fetal weights were reduced in rats and rabbits given doses of
≥ 10 mg/kg/day and 50 mg/kg/day, respectively. These doses are ≤ 1.2-fold and ≤ 12-fold the human dose
of 40 mg every 12 hours based on body surface area, respectively. There were no
effects of oxymorphone hydrochloride on intrauterine survival in rats at doses
≤ 25 mg/kg/day, or rabbits at ≤ 50 mg/kg/day in these studies (see Non-teratogenic
Effects, below). In a study that was conducted prior to the establishment
of Good Laboratory Practices (GLP) and not according to current recommended
methodology, a single subcutaneous injection of oxymorphone hydrochloride on
gestation day 8 was reported to produce malformations in offspring of hamsters
that received 15.5-fold the human dose of 40 mg every 12 hours based on body
surface area. This dose also produced 20% maternal lethality.
Oxymorphone hydrochloride administration to female rats
during gestation in a pre-and postnatal developmental toxicity study reduced
mean litter size (18%) at a dose of 25 mg/kg/day, attributed to an increased
incidence of stillborn pups. An increase in neonatal death occurred at ≥ 5
mg/kg/day. Post-natal survival of the pups was reduced throughout weaning
following treatment of the dams with 25 mg/kg/day. Low pup birth weight and
decreased postnatal weight gain occurred in pups born to oxymorphone-treated
pregnant rats given a dose of 25 mg/kg/day. This dose is ≤ 3-fold higher than the
human dose of 40 mg every 12 hours on a body surface area basis.
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. OPANA ER 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.
It is not known whether oxymorphone is excreted in human
milk. Because many drugs, including some opioids, are excreted in human milk,
caution should be exercised when OPANA ER is administered to a nursing woman.
Monitor infants who may be exposed to OPANA ER through breast milk for excess
sedation and respiratory depression. Withdrawal symptoms can occur in
breast-fed infants when maternal administration of an opioid analgesic is
stopped, or when breast-feeding is stopped.
The safety and effectiveness of OPANA ER in patients
below the age of 18 years have not been established.
Of the total number of subjects in clinical studies of
oxymorphone hydrochloride extended-release tablets, 27% were 65 and over, while
9% were 75 and over. No overall differences in effectiveness were observed between
these subjects and younger subjects. There were several adverse events that
were more frequently observed in subjects 65 and over compared to younger
subjects. These adverse events included dizziness, somnolence, confusion, and
nausea. On average, age greater than 65 years was associated with a 1.4-fold
increase in oxymorphone AUC and a 1.5-fold increase in Cmax. Initiate dosing
with OPANA ER in patients 65 years of age and over using the 5 mg dose and
monitor closely for signs of respiratory and central nervous system depression
when initiating and titrating OPANA ER. For patients on prior opioid therapy,
start at 50% of the starting dose for a younger patient on prior opioids and
Patients with mild hepatic impairment have an increase in
oxymorphone bioavailability of 1.6-fold. In opioid-naÃ¯ve patients with mild
hepatic impairment, initiate OPANA ER using the 5 mg dose and monitor closely
for respiratory and central nervous system depression. OPANA ER is contraindicated
for patients with moderate and severe hepatic impairment [see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION]. For
patients on prior opioid therapy, start at the 50% of the dose for that a
patient with normal hepatic function on prior opioids and titrate slowly.
Patients with moderate to severe renal impairment were
shown to have an increase in oxymorphone bioavailability ranging from 5765% [see
CLINICAL PHARMACOLOGY]. Start opioid-naÃ¯ve patients with the 5 mg dose of
OPANA ER and titrate slowly while closely monitoring for respiratory and
central nervous system depression [see DOSAGE AND ADMINISTRATION]. For
patients on prior opioid therapy, start at 50% of the dose for a patient with
normal renal function on prior opioids and titrate slowly.