Risk Of Medication Errors
DILAUDID-HP INJECTION is a 10 mg/mL concentrated solution
of hydromorphone, and is intended for use in opioid-tolerant patients only.
Patients considered opioid tolerant are those who are taking at least 60 mg
oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day,
8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic
dose of another opioid for one week or longer.
Do not confuse DILAUDID-HP INJECTION with standard
parenteral formulations of DILAUDID INJECTION (0.5 mg/0.5 mL, 1 mg/mL, 2 mg/mL,
4 mg/mL) or other opioids, as overdose and death could result.
Addiction, Abuse, And Misuse
DILAUDID INJECTION and DILAUDID-HP INJECTION contain
hydromorphone, a Schedule II controlled substance. As an opioid, DILAUDID
INJECTION and DILAUDID-HP INJECTION 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 DILAUDID INJECTION
or DILAUDID-HP INJECTION. Addiction can occur at recommended dosages and if the
drug is misused or abused.
Assess each patient's risk for opioid addiction, abuse,
or misuse prior to prescribing DILAUDID INJECTION or DILAUDID-HP INJECTION, and
monitor all patients receiving DILAUDID INJECTION or DILAUDID-HP INJECTION 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 DILAUDID INJECTION or DILAUDID-HP INJECTION, but use in such patients
necessitates intensive counseling about the risks and proper use of DILAUDID
INJECTION or DILAUDID-HP INJECTION along with intensive monitoring for signs of
addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion. Consider these risks
when prescribing or dispensing DILAUDID INJECTION or DILAUDID-HP INJECTION.
Strategies to reduce these risks include prescribing the drug in the smallest
appropriate quantity. 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 DILAUDID INJECTION or
DILAUDID-HP INJECTION, the risk is greatest during the initiation of therapy or
following a dosage increase. Monitor patients closely for respiratory
depression, especially within the first 24-72 hours of initiating therapy with
and following dosage increases of DILAUDID INJECTION or DILAUDID-HP INJECTION.
To reduce the risk of respiratory depression, proper
dosing and titration of DILAUDID INJECTION or DILAUDIDHP INJECTION are
essential [see DOSAGE AND ADMINISTRATION]. Overestimating the DILAUDID
INJECTION or DILAUDID-HP INJECTION dosage when converting patients from another
opioid product can result in a fatal overdose with the first dose.
DILAUDID-HP INJECTION is for use in opioid-tolerant
patients only. Administration of this formulation may cause fatal respiratory
depression when administered to patients who are not tolerant to the
respiratory depressant effects of opioids.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of DILAUDID INJECTION or DILAUDID-HP
INJECTION 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 Counseling
Risks From Concomitant Use With Benzodiazepines Or Other
Profound sedation, respiratory depression, coma, and
death may result from the concomitant use of DILAUDID or DILAUDID-HP Injection
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 DILAUDID or DILAUDID-HP Injection is
used with benzodiazepines or other CNS depressants (including alcohol and
illicit drugs). Advise patients not to drive or operate heavy machinery until
the effects of concomitant use of the benzodiazepine or other CNS depressant
have been determined. Screen patients for risk of substance use disorders,
including opioid abuse and misuse, and warn them of the risk for overdose and
death associated with the use of additional CNS depressants including alcohol
and illicit drugs [see DRUG INTERACTIONS and PATIENT INFORMATION].
Life-Threatening Respiratory Depression In Patients With Chronic
Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients
The use of DILAUDID INJECTION or DILAUDID-HP INJECTION 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
DILAUDID INJECTION or DILAUDID-HP INJECTION 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 DILAUDID INJECTION or DILAUDID-HP INJECTION [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 such patients closely, particularly when
initiating and titrating DILAUDID INJECTION or DILAUDID-HP INJECTION and when
DILAUDID INJECTION or DILAUDID-HP INJECTION are 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 insufficiency.
DILAUDID INJECTION and DILAUDID-HP INJECTION 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 DILAUDID INJECTION
or DILAUDID-HP INJECTION. In patients with circulatory shock, DILAUDID
INJECTION or DILAUDID-HP INJECTION may cause vasodilation that can further
reduce cardiac output and blood pressure. Avoid the use of DILAUDID INJECTION
or DILAUDID-HP INJECTION in patients with circulatory shock.
Risks Of Use In Patients With Increased Intracranial
Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness
In patients who may be susceptible to the intracranial
effects of CO2 retention (e.g., those with evidence of increased intracranial
pressure or brain tumors), DILAUDID INJECTION or DILAUDID-HP INJECTION 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 DILAUDID
INJECTION or DILAUDID-HP INJECTION.
Opioids may also obscure the clinical course in a patient
with a head injury. Avoid the use of DILAUDID INJECTION or DILAUDID-HP
INJECTION in patients with impaired consciousness or coma.
Risks Of Use In Patients With Gastrointestinal Conditions
DILAUDID INJECTION and DILAUDID-HP INJECTION are
contraindicated in patients with known or suspected gastrointestinal
obstruction, including paralytic ileus.
The hydromorphone in DILAUDID INJECTION and DILAUDID-HP
INJECTION 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 worsening symptoms.
Increased Risk Of Seizures In Patients With Seizure
The hydromorphone in DILAUDID INJECTION and DILAUDID-HP
INJECTION 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 DILAUDID INJECTION or DILAUDID-HP
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 DILAUDID INJECTION and DILAUDID-HP INJECTION. In these
patients, mixed agonist/antagonist and partial agonist analgesics may reduce
the analgesic effect and/or precipitate withdrawal symptoms [see DRUG
When discontinuing DILAUDID INJECTION or DILAUDID-HP
INJECTION, in a physically-dependent patient, gradually taper the dosage [see DOSAGE
AND ADMINISTRATION]. Do not abruptly discontinue DILAUDID INJECTION or
DILAUDID-HP INJECTION in these patients [see Drug Abuse And Dependence].
Risks Of Driving And Operating Machinery
DILAUDID INJECTION and DILAUDID-HP INJECTION 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
DILAUDID INJECTION or DILAUDID-HP INJECTION and know how they will react to the
medication [see Patient Counseling Information].
DILAUDID INJECTION and DILAUDID-HP INJECTION contain
sodium metabisulfite, a sulfite that may cause allergic-type reactions
including anaphylactic symptoms and life-threatening or less severe asthmatic
episodes in certain susceptible people. The overall prevalence of sulfite
sensitivity in the general population is unknown and probably low. Sulfite
sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
Increased Risk Of Hypotension And Respiratory Depression With
Rapid Intravenous Administration
DILAUDID INJECTION and DILAUDID-HP INJECTION may be given
intravenously, but the injection should be given very slowly. Rapid intravenous
injection of opioid analgesics increases the possibility of side effects such
as hypotension and respiratory depression [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long term studies in animals to evaluate the carcinogenic
potential of hydromorphone have not been conducted.
Hydromorphone was positive in the mouse lymphoma assay in
the presence of metabolic activation, but was negative in the mouse lymphoma
assay in the absence of metabolic activation. Hydromorphone was not mutagenic
in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone
was not clastogenic in either the in vitro human lymphocyte chromosome
aberration assay or the in vivo mouse micronucleus assay.
Impairment Of Fertility
Reduced implantation sites and viable fetuses were noted
at 2.1 times the human daily dose of 32 mg/day in a study in which female rats
were treated orally with 1.75, 3.5, or 7 mg/kg/day hydromorphone hydrochloride
(0.5, 1.1, or 2.1 times a human daily dose of 24 mg/day (HDD) based on body
surface area) beginning 14 days prior to mating through Gestation Day 7 and
male rats were treated with the same hydromorphone hydrochloride doses beginning
28 days prior to and throughout mating.
Use In Specific Populations
Prolonged use of opioid
analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see WARNINGS
AND PRECAUTIONS]. There are no available data with DILAUDID injection in
pregnant women to inform a drug-associated risk for major birth defects and
In animal reproduction studies,
reduced postnatal survival of pups, and decreased were noted following oral
treatment of pregnant rats with hydromorphone during gestation and through
lactation at doses 0.8 times the human daily dose of 24 mg/day (HDD),
respectively. In published studies, neural tube defects were noted following
subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times
the HDD and soft tissue and skeletal abnormalities were noted following
subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No
malformations were noted at 4 or 40.5 times the HDD in pregnant rats or
rabbits, respectively [see 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.
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. DILAUDID INJECTION or
DILAUDID-HP INJECTION is not recommended for use in pregnant women during or
immediately prior to labor, when other analgesic techniques are more
appropriate. Opioid analgesics, including DILAUDID INJECTION or DILAUDID-HP
INJECTION, 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.
Pregnant rats were treated with
hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of
1, 5, or 10 mg/kg/day (0.4, 2, or 4 times the HDD of 24 mg based on body
surface area, respectively). Maternal toxicity was noted in all treatment
groups (reduced food consumption and body weights in the two highest dose
groups). There was no evidence of malformations or embryotoxicity reported.
Pregnant rabbits were treated
with hydromorphone hydrochloride from Gestation Day 7 to 19 via oral gavage
doses of 10, 25, or 50 mg/kg/day (8.1, 20.3, or 40.5 times the HDD of 24 mg
based on body surface area, respectively). Maternal toxicity was noted in the
two highest dose groups (reduced food consumption and body weights). There was
no evidence of malformations or embryotoxicity reported.
In a published study, neural
tube defects (exencephaly and cranioschisis) were noted following subcutaneous
administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation
Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on
body surface area). The findings cannot be clearly attributed to
maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the
human daily dose of 24 mg/day).
In a published study, CF-1 mice were treated
subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone
hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body
surface area) via implanted osmotic pumps during organogenesis (Gestation Days
7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed
ventricles and retina), and skeletal variations (split supraoccipital,
checkerboard and split sternebrae, delayed ossification of the paws and ectopic
ossification sites) were observed at doses 3 times the human dose of 24 mg/day
based on body surface area. The findings cannot be clearly attributed to
Increased pup mortality and decreased pup body weights
were noted at 0.8 and 2 times the human daily dose of 24 mg in a study in which
pregnant rats were treated with hydromorphone hydrochloride from Gestation Day
7 to Lactation Day 20 via oral gavage doses of 0, 0.5, 2, or 5 mg/kg/day (0.2,
0.8, or 2 times the HDD of 24 mg based on body surface area, respectively).
Maternal toxicity (decreased food consumption and body weight gain) was also
noted at the two highest doses tested.
Low levels of opioid analgesics have been detected in
human milk. The developmental and health benefits of breastfeeding should be
considered along with the mother's clinical need for DILAUDID INJECTION or
DILAUDID-HP INJECTION and any potential adverse effects on the breastfed infant
from DILAUDID INJECTION or DILAUDID-HP INJECTION or from the underlying
Monitor infants exposed to DILAUDID INJECTION or
DILAUDID-HP INJECTION through breast milk for excess sedation and respiratory
depression. Withdrawal symptoms can occur in breastfed infants when maternal
administration of hydromorphone 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, Nonclinical Toxicology].
The safety and effectiveness of DILAUDID INJECTION and
DILAUDID-HP INJECTION in pediatric patients has not been established.
Elderly patients (aged 65 years or older) may have
increased sensitivity to hydromorphone. 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 DILAUDID INJECTION or DILAUDID-HP INJECTION slowly in geriatric patients and
monitor closely for signs of central nervous system and respiratory depression [see
WARNINGS AND PRECAUTIONS].
Hydromorphone 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.
The pharmacokinetics of hydromorphone are affected by
hepatic impairment. Due to increased exposure of hydromorphone, patients with
moderate hepatic impairment should be started at one-fourth to one-half the
recommended starting dose depending on the degree of hepatic dysfunction and
closely monitored during dose titration. The pharmacokinetics of hydromorphone
in patients with severe hepatic impairment has not been studied. A further
increase in Cmax and AUC of hydromorphone in this group is expected and should
be taken into consideration when selecting a starting dose [see CLINICAL
The pharmacokinetics of hydromorphone are affected by
renal impairment. Start patients with renal impairment on one-fourth to
one-half the usual starting dose depending on the degree of impairment.
Patients with renal impairment should be closely monitored during dose
titration [see CLINICAL PHARMACOLOGY].