Included as part of the PRECAUTIONS section.
Respiratory depression is the chief hazard of OPANA.
Respiratory depression may occur more frequently in elderly or debilitated
patients as well as in those suffering from conditions accompanied by hypoxia
or hypercapnia, when even moderate therapeutic doses may dangerously decrease
Administer OPANA with extreme caution to patients with
conditions accompanied by hypoxia, hypercapnia, or decreased respiratory
reserve such as: asthma, chronic obstructive pulmonary disease or cor
pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, CNS
depression, or coma. In these patients, even usual therapeutic doses of
oxymorphone may decrease respiratory drive while simultaneously increasing
airway resistance to the point of apnea. Consider alternative non-opioid
analgesics and use OPANA only under careful medical supervision at the lowest
effective dose in such patients.
Misuse, Abuse, And Diversion Of Opioids
OPANA contains oxymorphone, a mu opioid agonist and a
Schedule II controlled substance with an abuse liability similar to morphine.
Opioid agonists are sought by drug abusers and people with addiction disorders
and are subject to criminal diversion.
Oxymorphone can be abused in a manner similar to other
opioid agonists, legal or illicit. This issue should be considered when
prescribing or dispensing oxymorphone in situations where the physician or
pharmacist is concerned about an increased risk of misuse, abuse, or diversion.
OPANA tablets may be abused by crushing, chewing,
snorting, or injecting the product. These practices pose a significant risk to
the abuser that could result in overdose and death [see Drug Abuse and Dependence].
OPANA may be targeted for theft and diversion. Healthcare
professionals should contact their State Medical Board, State Board of
Pharmacy, or State Control Board for information on how to detect or prevent
diversion of this product, and security requirements for storing and handling
Healthcare professionals should advise patients to store
OPANA in a secure place, preferably locked and out of the reach of children and
Concerns about abuse, misuse, diversion and addiction
should not prevent the proper management of pain.
Additive CNS Depressant Effects
The concomitant use of other CNS depressants including
other opioids, general anesthetics, phenothiazines, other tranquilizers,
sedatives, hypnotics, and alcohol with oxymorphone may produce increased
depressant effects including hypoventilation, hypotension, profound sedation,
coma and death [see DRUG INTERACTIONS].
Use In Patients With
Head Injury And Increased Intracranial Pressure
In the presence of head injury, intracranial lesions or a
preexisting increase in intracranial pressure, the respiratory depressant
effects of opioid analgesics and their potential to elevate cerebrospinal fluid
pressure (resulting from vasodilation following CO2 retention) may be markedly
exaggerated. Furthermore, opioid analgesics can produce effects on papillary response
and consciousness, which may obscure neurologic signs of further increases in
intracranial pressure in patients with head injuries.
Administer OPANA with extreme caution in patients who may
be particularly susceptible to the intracranial effects of CO2 retention, such
as those with evidence of increased intracranial pressure or impaired
Opioids may obscure the clinical course of a patient with
a head injury and should be used only if clinically warranted.
OPANA, like all opioid analgesics, may cause severe
hypotension in a patient whose ability to maintain blood pressure has been
compromised by a depleted blood volume, or after concurrent administration with
drugs such as phenothiazines or other agents that compromise vasomotor tone.
Administer OPANA with caution to patients in circulatory shock, since
vasodilation produced by the drug may further reduce cardiac output and blood
A study of extended-release oxymorphone tablets in
patients with hepatic disease indicated greater plasma concentrations than in
those with normal hepatic function [see CLINICAL PHARMACOLOGY]. Use
OPANA with caution in patients with mild impairment, starting with the lowest
dose and titrating slowly while carefully monitoring for side effects [see DOSAGE
AND ADMINISTRATION]. OPANA is contraindicated in patients with
moderate or severe hepatic impairment.
Special Risk Groups
Use OPANA with caution in the following conditions:
adrenocortical insufficiency (e.g., Addison's disease), prostatic hypertrophy
or urethral stricture, severe impairment of pulmonary or renal function, and
Opioids may aggravate convulsions in patients with
convulsive disorders, and may induce or aggravate seizures in some clinical
Opioids diminish propulsive peristaltic waves in the
gastrointestinal tract. Monitor for decreased bowel motility in post-operative
patients receiving opioids. The administration of OPANA may obscure the
diagnosis or clinical course in patients with acute abdominal conditions. OPANA
is contraindicated in patients with paralytic ileus.
Use In Pancreatic/Biliary Tract Disease
OPANA, like other opioids, may cause spasm of the
sphincter of Oddi and should be used with caution in patients with biliary
tract disease, including acute pancreatitis.
Driving And Operating Machinery
Opioid analgesics impair the mental and physical
abilities needed to perform potentially hazardous activities such as driving a
car or operating machinery.
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 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 dose in
male rats was 0.34-fold and at the 25 mg/kg/day dose in female rats was 1.5fold
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 ≤ g/plate, or in an in vitro mammalian cell chromosome aberration assay performed
with human peripheral blood lymphocytes at concentrations ≤ 5000 ≤ g/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 of ≤ 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 did not affect reproductive function or sperm
parameters in male rats at any dose tested ( ≤ 50 mg/kg/day). 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 0.8 times a total human daily dose
of 120 mg based on a body surface area. The dose of oxymorphone that produced
no adverse effects on reproductive findings in female rats (i.e., NOAEL) is
0.4-times a total human daily dose of 120 mg based on body surface area.
Use In Specific Populations
The safety of using oxymorphone in pregnancy has not been
established with regard to possible adverse effects on fetal development. The
use of OPANA in pregnancy, in nursing mothers, or in women of child-bearing
potential requires that the possible benefits of the drug be weighted against
the possible hazards to the mother and the child.
Pregnancy Category C
There are no adequate and well-controlled studies of
oxymorphone in pregnant women. In animal studies, oxymorphone caused decreased
fetal and pup weights, an increase in stillbirth, and a decrease in postnatal
pup survival at maternal oxymorphone doses equivalent to 0.4 to 4 times the
human daily dose of 120 mg (Based on body surface area). OPANA should be used
during pregnancy only if the potential benefit justifies the potential risk to
In embryo-fetal developmental toxicity studies, pregnant
rats and rabbits received oxymorphone hydrochloride at doses up to about 2
times (rats) and 8 times (rabbits) total human daily dose of 120 mg (based on
body surface area). No malformations occurred, but reduced fetal weights
occurred at maternal doses of 0.8 (rat) and 4 (rabbit) times the total human
daily dose of 120 mg (based on body surface area). There were no adverse
developmental effects in rats that received 0.4 times or rabbits that received
less than 4 times the total human dose. There were no effects of oxymorphone
hydrochloride on intrauterine survival at doses in rats ≤ 2 times, or in
rabbits at ≤ 8 times the human dose (see Non-teratogenic Effects, below). In a study 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 produced malformations in offspring of
hamsters that received a dose equivalent to 10 times the total human daily dose
of 120 mg (based on body surface area). This dose also produced 83% maternal
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 increase in
the incidence of stillborn pups. An increase in neonatal death occurred at
doses ≤ 5 mg/kg/day (0.4 times a total human daily dose of 120 mg, based
on body surface area). Low pup birth weight, decreased post-natal weight gain,
and reduced post-natal survival of pups occurred following treatment of the
dams with 25 mg/kg/day (about 2 times a total human daily dose of 120 mg, based
on body surface area).
Prolonged use of opioid analgesics during pregnancy may
cause fetal-neonatal physical dependence. Neonatal withdrawal may occur.
Symptoms usually appear during the first days of life and may include
convulsions, irritability, excessive crying, tremors, hyperactive reflexes,
fever, vomiting, diarrhea, sneezing, yawning, and increased respiratory rate.
Labor And Delivery
Opioids cross the placenta and may produce respiratory
depression in neonates. OPANA is not recommended for use in women during and
immediately prior to labor, when use of shorter acting analgesics or other
analgesic techniques are more appropriate. Occasionally, opioid analgesics may
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 dilatation, which tends to
shorten labor. Neonates whose mothers received opioid analgesics during labor
should be observed closely for signs of respiratory depression. A specific
opioid antagonist, such as naloxone or nalmefene, should be available for
reversal of opioid-induced respiratory depression in the neonate.
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 is administered to a nursing woman.
Infants exposed to OPANA through breast milk should be monitored 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.
Safety and effectiveness of OPANA in pediatric patients
below the age of 18 years have not been established.
OPANA should be used with caution in elderly patients [see
Of the total number of subjects in clinical studies of
OPANA, 31% were 65 and over, while 7% 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. In general, dose
selection for elderly patients 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
In a study of extended-release oxymorphone tablets,
patients with mild hepatic impairment were shown to have an increase in
bioavailability of 1.6 fold. OPANA should be used with caution in patients with
mild impairment. These patients should be started with the lowest dose and
titrated slowly while carefully monitoring for side effects. OPANA is
contraindicated for patients with moderate and severe hepatic impairment [see
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION].
In a study of extended-release oxymorphone tablets,
patients with moderate to severe renal impairment were shown to have an
increase in bioavailability ranging from 57-65% [see CLINICAL PHARMACOLOGY].
Such patients should be started cautiously with lower doses of OPANA and
titrated slowly while monitoring for side effects [see DOSAGE AND ADMINISTRATION].