Included as part of the PRECAUTIONS section.
Addiction, Abuse, And Misuse
ROXYBOND contains oxycodone, a
Schedule II controlled substance. As an opioid, ROXYBOND exposes users to the
risks of addiction, abuse, and misuse [see Drug Abuse And Dependence].
Although the risk of addiction
in any individual is unknown, it can occur in patients appropriately prescribed
ROXYBOND. Addiction can occur at recommended dosages, when taken as directed,
and if the drug is misused or abused.
Assess each patient's risk for
opioid addiction, abuse, or misuse prior to prescribing ROXYBOND, and monitor
all patients receiving ROXYBOND for the 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 ROXYBOND, but use in such
patients necessitates intensive counseling about the risks and proper use of
ROXYBOND along with intensive monitoring for signs of addiction, abuse, and
Opioids are sought by drug
abusers and people with addiction disorders and are subject to criminal
diversion. Consider these risks when prescribing or dispensing ROXYBOND.
Strategies to reduce these risks include prescribing the drug in the smallest
appropriate quantity and advising the patient on the proper disposal of unused
drugs [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.
Opioid Analgesic Risk
Evaluation And Mitigation Strategy (REMS)
To ensure that the benefits of
opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food
and Drug Administration (FDA) has required a Risk Evaluation and Mitigation
Strategy (REMS) for these products. Under the requirements of the REMS, drug
companies with approved opioid analgesic products must make REMS-compliant
education programs available to healthcare providers. Healthcare providers are
strongly encouraged to do all of the following:
- Complete a REMS-compliant education program offered by an
accredited provider of continuing education (CE) or another education program
that includes all the elements of the FDA Education Blueprint for Health Care
Providers Involved in the Management or Support of Patients with Pain.
- Discuss the safe use, serious risks, and proper storage
and disposal of opioid analgesics with patients and/or their caregivers every
time these medicines are prescribed. The Patient Counseling Guide (PCG) can be
obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
- Emphasize to patients and their caregivers the importance
of reading the Medication Guide that they will receive from their pharmacist
every time an opioid analgesic is dispensed to them.
- Consider using other tools to improve patient, household,
and community safety, such as patient-prescriber agreements that reinforce
To obtain further information on the opioid analgesic
REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on
to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
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 ROXYBOND, 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 to 72 hours of initiating therapy with and following dosage increases
To reduce the risk of respiratory depression, proper
dosing and titration of ROXYBOND are essential [see DOSAGE AND
ADMINISTRATION]. Overestimating the ROXYBOND dosage when converting
patients from another opioid product can result in fatal overdose with the
Accidental ingestion of even one dose of ROXYBOND,
especially by children, can result in respiratory depression and death due to
an overdose of oxycodone.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of ROXYBOND 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 Of Concomitant Use Or Discontinuation Of Cytochrome
P450 3A4 Inhibitors And Inducers
Concomitant use of ROXYBOND with a CYP3A4 inhibitor, such
as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.,
ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma
concentrations of oxycodone and prolong opioid adverse reactions, which may
cause potentially fatal respiratory depression [see
Life-Threatening Respiratory Depression], particularly when an inhibitor is added
after a stable dose of ROXYBOND is achieved. Similarly, discontinuation of a
CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in
ROXYBOND-treated patients may increase oxycodone plasma concentrations and
prolong opioid adverse reactions. When using ROXYBOND with CYP3A4 inhibitors or
discontinuing CYP3A4 inducers in ROXYBOND-treated patients, monitor patients
closely at frequent intervals and consider dosage reduction of ROXYBOND until
stable drugs effects are achieved [see DRUG INTERACTIONS].
Concomitant use of ROXYBOND with CYP3A4 inducers or
discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma
concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal
syndrome in a patient who had developed physical dependence to oxycodone. When
using ROXYBOND with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor
patients closely at frequent intervals and consider increasing the opioid
dosage if needed to maintain adequate analgesia or if symptoms of opioid
withdrawal occur [see DRUG INTERACTIONS].
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of ROXYBOND 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 ROXYBOND is used with benzodiazepines
or other CNS depressants (including alcohol and illicit drugs). Advise patients
not to drive or operate dangerous 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].
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of ROXYBOND 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
ROXYBOND-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 ROXYBOND [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 because they may have
altered pharmacokinetics or altered clearance compared to younger, healthier patients
[see Life-Threatening Respiratory Depression].
Monitor patients closely, particularly when initiating
and titrating ROXYBOND and when ROXYBOND 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.
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
ROXYBOND 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 ROXYBOND. In patients with circulatory
shock, use of ROXYBOND may cause vasodilation that can further reduce cardiac
output and blood pressure. Avoid use of ROXYBOND 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), ROXYBOND may reduce the 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 ROXYBOND.
Opioids may obscure the clinical course in a patient with
a head injury. Avoid the use of ROXYBOND in patients with impaired
consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
ROXYBOND is contraindicated in patients with
gastrointestinal obstruction, including paralytic ileus.
The oxycodone in ROXYBOND 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 oxycodone in ROXYBOND 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 ROXYBOND 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 ROXYBOND. In these patients, mixed agonist/antagonist and
partial agonist analgesics may reduce the analgesic effect and/or precipitate
withdrawal symptoms [see DRUG INTERACTIONS].
When discontinuing ROXYBOND in a physically-dependent
patient, gradually taper the dosage [see DOSAGE AND ADMINISTRATION]. Do
not abruptly discontinue ROXYBOND in these patients [see Drug Abuse And Dependence].
Risks Of Driving And Operating Machinery
ROXYBOND 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 ROXYBOND 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
ROXYBOND, 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 ROXYBOND with others and to take steps to protect ROXYBOND from theft
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening
respiratory depression, including information that the risk is greatest when
starting ROXYBOND 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 develop.
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 ROXYBOND securely and to dispose of unused ROXYBOND by
flushing the tablets down the toilet or disposing of in accordance with local
state guidelines and/or regulations.
Interactions With Benzodiazepines And Other CNS
Inform patients and caregivers that potentially fatal
additive effects may occur if ROXYBOND 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 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 healthcare providers if they are
taking, or plan to take serotonergic medication [see DRUG INTERACTIONS].
Inform patients to avoid taking ROXYBOND while using any
drugs that inhibit monoamine oxidase. Patients should not start MAOIs while
taking ROXYBOND [see 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].
Important Administration Instructions
Instruct patients how to properly take ROXYBOND. Patients
should be advised not to adjust the dose of ROXYBOND without consulting the
prescribing healthcare provider [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Inform patients that ROXYBOND 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 sitting or lying
position) [see WARNINGS AND PRECAUTIONS].
Inform patients that anaphylaxis has been reported with
ingredients contained in ROXYBOND. 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 ROXYBOND 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
ROXYBOND can cause fetal harm and to inform their healthcare provider of a
known or suspected pregnancy [see Use In Specific Populations].
Advise nursing mothers to monitor infants for increased
sleepiness (more than usual), breathing difficulties, or limpness. Instruct
nursing mothers to seek immediate medical care if they notice these signs [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 Machinery
Inform patients that ROXYBOND may impair the ability to
perform potentially hazardous activities such as driving a car or operating
dangerous 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 PHARMACOLOGY].
Disposal Of Unused ROXYBOND
Advise patients to keep ROXYBOND in a secure place out of
reach of children. Advise patients to dispose of unused ROXYBOND by flushing
the tablets down the toilet or disposing in accordance with local state
guidelines and/or regulations.
Healthcare professionals can telephone Daiichi Sankyo,
Inc. (1-877-437-7763) for information on this product.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term studies have not been performed in animals to
evaluate the carcinogenic potential of oxycodone.
Oxycodone hydrochloride was genotoxic in an in vitro
mouse lymphoma assay in the presence of metabolic activation. There was no
evidence of genotoxic potential in an in vitro bacterial reverse mutation assay
(Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal
aberrations (in vivo mouse bone marrow micronucleus assay).
Impairment Of Fertility
Studies in animals to evaluate the potential impact of
oxycodone on fertility have not been conducted.
Use In Specific Populations
Prolonged use of opioid
analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS
AND PRECAUTIONS, Clinical Considerations]. There are reports of
respiratory depression when oxycodone is used during labor and delivery [see Clinical
There are no available data with ROXYBOND in
pregnant women to inform a drug-associated risk for adverse developmental
outcomes. Animal reproduction studies with oral administrations of oxycodone
hydrochloride in rats and rabbits during the period of organogenesis, at doses
2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal
evidence of teratogenicity or embryo-fetal toxicity. In several published
studies, treatment of pregnant rats with oxycodone at clinically relevant doses
and below, resulted in neurobehavioral effects in offspring [see Data].
Based on animal data, advise pregnant women of the potential risk to a fetus.
The estimated risk of major
birth defects and miscarriage for the indicated population is unknown. All
pregnancies have a background risk of birth defects, 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%
to 4% and 15% to 20%, respectively.
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. ROXYBOND is not recommended for use in
pregnant women during or immediately prior to labor, when other analgesic
techniques are more appropriate. Opioid analgesics, including ROXYBOND, 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.
Limited published data from
case-control and observational studies on oxycodone use during pregnancy are
inconsistent in their findings. Although some studies reported an increased
risk of congenital malformations, there was no consistent pattern of
malformations noted. In addition, multiple similar studies reported no
association. Methodological limitations of these studies, including small
sample size, recall bias, lack of information regarding dose and timing of
exposure and concomitant use of other medications, preclude a reliable
evaluation of the potential risk of adverse fetal outcomes with the use of oxycodone
In embryo-fetal development studies in rats and rabbits,
pregnant animals received oral doses of oxycodone hydrochloride administered
during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day,
respectively. These studies revealed no evidence of teratogenicity or
embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and
rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose
of 60 mg/day, respectively, on a mg/m² basis. In published studies, offspring
of pregnant rats administered oxycodone during gestation have been reported to
exhibit neurobehavioral effects including altered stress responses, increased
anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal
Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m² basis)
and altered learning and memory (15 mg/kg/day orally from breeding through
parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m² basis).
Lactation studies have not been conducted with ROXYBOND.
Published lactation studies report that oxycodone is present in human milk [see
Data]. There are reports of central nervous system depression in infants
who are breastfed by mothers taking oxycodone. There is no information on the
effects of oxycodone on milk production. The developmental and health benefits
of breastfeeding should be considered along with the mother's clinical need for
ROXYBOND and any potential adverse effects on the breastfed infant from
ROXYBOND or from the underlying maternal condition.
Infants exposed to ROXYBOND through breast milk should be
monitored 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
PHARMACOLOGY, and Nonclinical Toxicology].
The safety and efficacy of ROXYBOND in pediatric patients
have not been evaluated.
Of the total number of subjects in clinical studies of
oxycodone hydrochloride, 20.8% (112/538) were 65 and over, while 7.2% (39/538)
were 75 and over. No overall differences in safety or effectiveness were
observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
Elderly patients (aged 65 years or older) may have increased
sensitivity to oxycodone. 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 ROXYBOND slowly in geriatric patients and monitor closely for signs of
central nervous system and respiratory depression [see WARNINGS AND PRECAUTIONS].
Oxycodone 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.
Because oxycodone is extensively metabolized in the
liver, its clearance may decrease in patients with hepatic impairment. Initiate
therapy in these patients with a lower than usual dosage of ROXYBOND and
titrate carefully. Monitor closely for adverse events such as respiratory
depression, sedation, and hypotension [see CLINICAL PHARMACOLOGY].
Because oxycodone is known to be substantially excreted
by the kidney, its clearance may decrease in patients with renal impairment.
Initiate therapy with a lower than usual dosage of ROXYBOND and titrate
carefully. Monitor closely for adverse events such as respiratory depression,
sedation, and hypotension [see CLINICAL PHARMACOLOGY].