NDC 59011-452 Dilaudid

NDC Product Code 59011-452

NDC CODE: 59011-452

Proprietary Name: Dilaudid What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This medication is used to help relieve moderate to severe pain. Hydromorphone belongs to a class of drugs known as opioid analgesics. It works in the brain to change how your body feels and responds to pain.

Product Characteristics

Color(s):
ORANGE (C48331)
Shape: ROUND (C48348)
Size(s):
5 MM
Imprint(s):
P;2
Score: 2

NDC Code Structure

  • 59011 - Purdue Pharma Lp
    • 59011-452 - Dilaudid
This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Dilaudid with NDC 59011-452 is a product labeled by Purdue Pharma Lp. The product's dosage form is and is administered via form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 897657, 897658, 897696, 897698, 897702, 897704, 897710 and 897712.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)
  • METHYLPARABEN (UNII: A2I8C7HI9T)
  • PROPYLPARABEN (UNII: Z8IX2SC1OH)
  • SUCROSE (UNII: C151H8M554)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • SODIUM METABISULFITE (UNII: 4VON5FNS3C)
  • D&C RED NO. 30 (UNII: 2S42T2808B)
  • D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • SODIUM METABISULFITE (UNII: 4VON5FNS3C)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Purdue Pharma Lp
Labeler Code: 59011
Start Marketing Date: 01-01-1956 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2018 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Information for Patients

Hydromorphone

Hydromorphone is pronounced as (hye'' droe mor' fone)

Why is hydromorphone medication prescribed?
Hydromorphone is used to relieve pain. Hydromorphone extended-release tablets are used to relieve severe pain in people who are expected to need pain medication around th...
[Read More]

* Please review the disclaimer below.

Dilaudid Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Risk Of Medication Errors; Addiction, Abuse, And Misuse; Life-Threatening Respiratory Depression; Accidental Ingestion; Neonatal Opioid Withdrawal Syndrome; Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants

  • Risk
  • Of Medication ErrorsEnsure accuracy
  • When prescribing, dispensing, and administering DILAUDID Oral Solution.
  • Dosing errors due to confusion between mg and mL can result in accidental
  • Overdose and death [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].Addiction, Abuse, and MisuseDILAUDID Oral Solution and DILAUDID Tablets expose patients
  • And other users to the risks of opioid addiction, abuse, and misuse,
  • Which can lead to overdose and death. Assess each patient’s risk prior
  • To prescribing DILAUDID Oral Solution or DILAUDID Tablets, and monitor
  • All patients regularly for the development of these behaviors and
  • Conditions [see Warnings and Precautions (5.2)].Life-Threatening Respiratory DepressionSerious, life-threatening, or fatal respiratory
  • Depression may occur with use of DILAUDID Oral Solution and DILAUDID
  • Tablets. Monitor for respiratory depression, especially during initiation
  • Of DILAUDID Oral Solution or DILAUDID Tablets or following a dose
  • Increase [see Warnings and Precautions (5.3)].Accidental IngestionAccidental ingestion of even one dose of DILAUDID Oral Solution
  • Or DILAUDID Tablets, especially by children, can result in a fatal
  • Overdose of hydromorphone [see Warnings and Precautions (5.3)]Neonatal Opioid Withdrawal SyndromeProlonged use of DILAUDID Oral Solution or DILAUDID
  • Tablets during pregnancy can result in neonatal opioid withdrawal
  • Syndrome, which 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 [see Warnings and Precautions (5.4)]Risks
  • From Concomitant Use With Benzodiazepines Or Other CNS DepressantsConcomitant use of opioids with benzodiazepines
  • Or other central nervous system (CNS) depressants, including alcohol,
  • May result in profound sedation, respiratory depression, coma, and
  • Death [see Warnings and Precautions (5.5), Drug Interactions (7)].Reserve concomitant prescribing
  • Of DILAUDID Oral Solution OR DILAUDID Tablets and benzodiazepines
  • Or other CNS depressants for use in patients for whom alternative
  • Treatment options are inadequate.Limit dosages and durations to
  • The minimum required.Follow patients for signs and symptoms
  • Of respiratory depression and sedation.

1 Indications And Usage

  • DILAUDID Oral Solution
  • And DILAUDID Tablets are indicated for the management of pain severe
  • Enough to require an opioid analgesic and for which alternative treatments
  • Are inadequate.Limitations
  • Of UseBecause of the risks
  • Of addiction, abuse, and misuse with opioids, even at recommended
  • Doses [see Warnings and Precautions (5.2)], reserve DILAUDID Oral Solution and DILAUDID
  • Tablets for use in patients for whom alternative treatment options
  • [e.g., non-opioid analgesics or opioid combination products]:Have not been tolerated, or are not expectedto
  • Be tolerated,Have not provided adequate analgesia,
  • Or are not expected to provide adequate analgesia

2.1 Important Dosage And Administration Instructions

  • Ensure accuracy
  • When prescribing, dispensing, and administering DILAUDID Oral Solution
  • To avoid dosing errors due to confusion between mg and mL, which could
  • Result in accidental overdose and death. Ensure the proper dose is
  • Communicated and dispensed. When writing prescriptions, include both
  • The total dose in mg and the total dose in volume.Instruct patients to obtain a calibrated measuring cup/syringe for
  • Administering DILAUDID Oral Solution to ensurethat the dose is measured
  • And administered accurately.Do not use household
  • Teaspoons or tablespoons to measure DILAUDID Oral Solution, as using
  • A tablespoon instead of a teaspoon could lead to overdosage [see Warnings and Precautions (5.1)].Use the lowest effective dosage for the
  • Shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].Initiate the dosing regimen for each
  • Patient individually, taking into account the patient's severity of
  • Pain, patient response, prior analgesic treatment experience, and
  • Risk factors for addiction, abuse, and misuse [see Warnings
  • And Precautions (5.2)].Monitor patients closely for respiratory
  • Depression, especially within the first 24-72 hours of initiating
  • Therapy and following dosage increases with DILAUDID Oral Solution
  • Or DILAUDID Tablets and adjust the dosage accordingly[see
  • Warnings and Precautions (5.3)].

2.2 Initial Dosage

Initiating
Treatment with DILAUDID Oral Solution or DILAUDID TabletsDilaudid Oral SolutionInitiate treatment with DILAUDID Oral Solution in a dosing range
of one-half (2.5 mL to two teaspoonsful (10 mL (2.5 mg - 10 mg) every
3 to 6 hours as needed for pain.Dilaudid TabletsInitiate treatment with DILAUDID Tablets in a dosing
range of 2 mg to 4 mg, orally, every 4 to 6 hours.Conversion from Other Opioids to DILAUDID Oral Solution
or DILAUDID TabletsThere is inter-patient
variability in the potency of opioid drugs and opioid formulations.
Therefore, a conservative approach is advised when determining the
total daily dosage of DILAUDID Oral Solution or DILAUDID Tablets.
It is safer to underestimate a patient’s 24-hour DILAUDID dosage than
to overestimate the 24-hour dosage and manage an adverse reaction
due to overdose.In general, it is safest
to start DILAUDID therapy by administering half of the usual starting
dose every 3-6 hours for DILAUDID Oral Solution; and every 4-6 hours
for DILAUDID Tablets. The dose of DILAUDID can be gradually adjusted
until adequate pain relief and acceptable side effects have been achieved
[See Dosage and Administration (2.4)].Conversion
from DILAUDID Oral Solution or DILAUDID Tablets to Extended-Release
Hydromorphone HydrochlorideThe relative
bioavailability of DILAUDID Oral Solution and DILAUDID Tablets compared
to extended-release hydromorphone hydrochloride is unknown, so conversion
to extended-release tablets must be accompanied by close observation
for signs of excessive sedation and respiratory depression.

2.3 Dosage Modifications In Patients With Hepatic Impairment

Initiate
treatment with one-fourth to one-half the usual DILAUDID starting
dose depending on the degree of impairment [see Use in Specific
Populations (8.6), and Clinical Pharmacology
(12.3)].

2.4 Dosage Modifications In Patients With Renal Impairment

Initiate
treatment with one-fourth to one-half the usual DILAUDID starting
dose depending on the degree of impairment [see Use in Specific
Populations (8.7), and Clinical Pharmacology
(12.3)].

2.5 Titration And Maintenance Of Therapy

Individually titrate DILAUDID Oral Solution or DILAUDID Tablets to
a dose that provides adequate analgesia and minimizes adverse reactions.
Continually reevaluate patients receiving DILAUDID Oral Solution
or DILAUDID Tablets to assess the maintenance of pain control and
the relative incidence of adverse reactions, as well as monitoring
for the development of addiction, abuse, or misuse [see Warnings
and Precautions (5.2)].
Frequent communication is important among the prescriber, other members
of the healthcare team, the patient, and the caregiver/family during
periods of changing analgesic requirements, including initial titration.If the level of pain increases after dosage stabilization, attempt
to identify the source of increased pain before increasing the DILAUDID
Oral Solution or DILAUDID Tablets dosage. If unacceptable opioid-related
adverse reactions are observed, consider reducing the dosage. Adjust
the dosage to obtain an appropriate balance between management of
pain and opioid-related adverse reactions.For chronic pain, doses should be administered around-the-clock.
A supplemental dose of 5-15% of the total daily usage may be administered
every two hours on an as-needed basis.

2.6 Discontinuation Of Dilaudid Oral Solution Or Dilaudid Tablets

When a patient
who has been taking DILAUDID Oral Solution or DILAUDID Tablets regularly
and may be physically dependent no longer requires therapy with DILAUDID,
taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring
carefully for signs and symptoms of withdrawal. If the patient develops
these signs and symptoms, raise the dose to the previous level and
taper more slowly, either by increasing the interval between decreases,
decreasing the amount of change in dose, or both . Do not abruptly
discontinue DILAUDID Oral Solution or DILAUDID Tablets in a physically
dependent patient. [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

3 Dosage Forms And Strengths

  • DILAUDID Oral Solution: 5
  • Mg/5 mL (1 mg/mL) of hydromorphone hydrochloride in a clear, colorless
  • To pale yellow, slightly viscous liquid.DILAUDID Tablets:2 mg tablets (light orange, round, flat-faced tablets, with
  • Beveled edges, debossed with a “P” on one side and the number “2”
  • On the opposite side)4 mg tablets (light yellow, round, flat-faced tablets, with
  • Beveled edges, debossed with a “P” on one side and the number “4”
  • On the opposite side)8 mg tablets (white, triangular shaped tablets, debossed
  • With a “P” and an inverted “P” separated with a bisect on one side
  • Of the tablet and debossed with the number “8” on the other side of
  • The tablet)

4 Contraindications

  • DILAUDID
  • Oral Solution and DILAUDID Tablets are contraindicated in patients
  • With:Significant respiratory depression [see Warnings and Precautions (5.6)]Acute or severe bronchial asthma in an
  • Unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)]Known or suspected gastrointestinal obstruction,
  • Including paralytic ileus [see Warnings and Precautions (5.10)]Hypersensitivity to hydromorphone, hydromorphone
  • Salts, any other components of the product, or sulfite-containing
  • Medications (e.g., anaphylaxis) [see Warnings and Precautions
  • (5.15) Adverse Reactions (6.1)]

5.1 Risk Of Accidental Overdose And Death Due To Medication Errors

Dosing errors
can result in accidental overdose and death. Ensure that the dose
is communicated clearly and dispensed accurately. A household teaspoon
or tablespoon is not an adequate measuring device. Given the inexactitude
of the household spoon measure and the possibility of using a tablespoon
instead of a teaspoon, which could lead to overdosage, the enclosed
measuring device should be used or a calibrated measuring device obtained
from the pharmacist. Health care providers should recommend a calibrated
device that can measure and deliver the prescribed dose accurately,
and instruct caregivers to use extreme caution in measuring the dosage.

5.2 Addiction, Abuse, And Misuse

DILAUDID Oral Solution
and DILAUDID Tablets contain hydromorphone, a Schedule II controlled
substance. As an opioid, DILAUDID exposes users to the risks of addiction,
abuse, and misuse [see Drug Abuse and Dependence (9)].Although
the risk of addiction in any individual is unknown, it can occur in
patients appropriately prescribed DILAUDID Oral Solution or DILAUDID
Tablets. 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
Oral Solution or DILAUDID Tablets, and monitor all patients receiving
DILAUDID Oral Solution or DILAUDID Tablets 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 Oral Solution or DILAUDID
Tablets, but use in such patients necessitates intensive counseling
about the risks and proper use of DILAUDID Oral Solution and DILAUDID
Tablets 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 Oral Solution or DILAUDID Tablets. 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 (17)]. 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.

5.3 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 (10)]. 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 Oral Solution or
DILAUDID Tablets, 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 Oral Solution
or DILAUDID Tablets.To reduce the risk of
respiratory depression, proper dosing and titration of DILAUDID Oral
Solution or DILAUDID Tablets are essential [see Dosage and
Administration (2)]. Overestimating
the DILAUDID Oral Solution or DILAUDID Tablets 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 DILAUDID Oral Solution or DILAUDID Tablets, especially
by children, can result in respiratory depression and death due to
an overdose of hydromorphone.

5.4 Neonatal Opioid Withdrawal Syndrome

Prolonged use of DILAUDID
Oral Solution or DILAUDID Tablets 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 (8.1), Patient Counseling Information (17)].

5.5 Risks From Concomitant Use With Benzodiazepines Or Other Cns Depressants

Profound sedation, respiratory depression, coma,
and death may result from the concomitant use of DILAUDID Oral Solution
and DILAUDID Tablets 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
Interactions (7)].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 Oral Solution or DILAUDID Tablets
are 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 (7), Patient
Counseling Information (17)]

5.6 Life-Threatening Respiratory Depression In Patients With Chronic Pulmonary Disease Or In Elderly, Cachectic, Or Debilitated Patients

The use of
DILAUDID Oral Solution or DILAUDID Tablets 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 Oral Solution-
or DILAUDID Tablet-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 Oral
Solution or DILAUDID Tablets [see Warnings and Precautions
(5.3)].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 Warnings and Precautions (5.3)].Monitor such
patients closely, particularly when initiating and titrating DILAUDID
Oral Solution or DILAUDID Tablets and when DILAUDID is given concomitantly
with other drugs that depress respiration [see Warnings and
Precautions (5.3)]. Alternatively,
consider the use of non-opioid analgesics in these patients.

5.7 Adrenal Insufficiency

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.

5.8 Severe Hypotension

DILAUDID Oral Solution
or DILAUDID Tablets 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 (7)]. Monitor these patients for signs of hypotension after initiating
or titrating the dosage of DILAUDID Oral Solution or DILAUDID Tablets.
In patients with circulatory shock, DILAUDID may cause vasodilation
that can further reduce cardiac output and blood pressure. Avoid the
use of DILAUDID Oral Solution or DILAUDID Tablets in patients with
circulatory shock.

5.9 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 Oral Solution or DILAUDID Tablets
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 Oral Solution or DILAUDID Tablets.Opioids may also obscure the clinical course in a patient with a
head injury. Avoid the use of DILAUDID in patients with impaired
consciousness or coma.

5.10 Risks Of Use In Patients With Gastrointestinal Conditions

DILAUDID
Oral Solution or DILAUDID Tablets are contraindicated in patients
with known or suspected gastrointestinal obstruction, including paralytic
ileus.The hydromorphone in
DILAUDID Oral Solution or DILAUDID Tablets 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.

5.11 Increased Risk Of Seizures In Patients With Seizure Disorders

The hydromorphone
in DILAUDID Oral Solution or DILAUDID Tablets may increase the frequency
of seizures in patients with seizure disorders, and may increase the
risk of seizures occuring in other clinical settings associated with
seizures. Monitor patients with a history of seizure disorders for
worsened seizure control during DILAUDID Oral Solution or DILAUDID
Tablets therapy.

5.12 Withdrawal

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
Oral Solution or DILAUDID Tablets. In these patients, mixed agonist/antagonist
and partial agonist analgesics may reduce the analgesic effect and/or
precipitate withdrawal symptoms [see Drug Interactions (7)].When discontinuing
DILAUDID Oral Solution or DILAUDID Tablets in a physically-dependent
patient, gradually taper the dosage [see Dosage and Administration
(2.6)]. Do not abruptly
discontinue DILAUDID Oral Solution or DILAUDID Tablets in these patients. [see Drug Abuse and Dependence (9.3)].

5.13 Risks Of Driving And Operating Machinery

DILAUDID
Oral Solution or DILAUDID Tablets 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 Oral Solution or DILAUDID Tablets and know how they will
react to the medication.

5.14 Sulfites

DILAUDID Oral Solution and DILAUDID Tablets 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. Use of DILAUDID Oral Solution and DILAUDID
Tablets is contraindicated in patients with hypersensitivity to sulfite-containing
medications.

6 Adverse Reactions

  • The following serious adverse reactions
  • Are described, or described in greater detail, in other sections:Addiction, Abuse, and Misuse [see Warnings and Precautions
  • (5.2)]Life-Threatening Respiratory Depression [see Warnings
  • And Precautions (5.3)]Neonatal Opioid Withdrawal Syndrome [see Warnings
  • And Precautions (5.4)]Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.5)Adrenal Insufficiency [see Warnings and Precautions
  • (5.7)]Severe Hypotension [see Warnings and Precautions
  • (5.8)]Gastrointestinal Adverse Reactions [see Warnings
  • And Precautions (5.10)]Seizures [see Warnings and Precautions (5.11)]Withdrawal [see Warnings and Precautions (5.12)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under
widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates
observed in clinical practice.Serious adverse reactions associated with
DILAUDID include respiratory depression and apnea and, to a lesser
degree, circulatory depression, respiratory arrest, shock, and cardiac
arrest.The most
common adverse effects are lightheadedness, dizziness, sedation, nausea,
vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and
pruritus. These effects seem to be more prominent in ambulatory patients
and in those not experiencing severe pain.Less Frequently Observed Adverse
ReactionsCardiac disorders: tachycardia, bradycardia, palpitationsEye disorders: vision blurred, diplopia, miosis, visual impairment Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal painGeneral disorders and administration
site conditions: weakness, feeling abnormal, chillsHepatobiliary disorders: biliary colicMetabolism and nutrition disorders: decreased appetiteMusculoskeletal and
connective tissue disorders: muscle rigidityNervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial
pressure, syncope, taste alteration, involuntary muscle contractions,
presyncopePsychiatric disorders: agitation, mood altered, nervousness,
anxiety, depression, hallucination, disorientation, insomnia, abnormal
dreamsRenal and
urinary disorders: urinary retention, urinary hesitation, antidiuretic
effectsRespiratory, thoracic, and mediastinal disorders: bronchospasm,
laryngospasmSkin and subcutaneous tissue disorders: urticaria, rash,
hyperhidrosisVascular disorders: flushing, hypotension, hypertension

6.2 Postmarketing Experience

The following adverse reactions have been
identified during post approval use of hydromorphone. Because these
reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.Confusional state, convulsions, drowsiness,
dyskinesia, dyspnea, erectile dysfunction, fatigue, hepatic enzymes
increased, hyperalgesia, hypersensitivity reaction, lethargy, myoclonus,
oropharyngeal swelling, peripheral edema, and somnolence.Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition,
have been reported during concomitant use of opioids with serotonergic
drugs.Adrenal insufficiency: Cases of adrenal insufficiency
have been reported with opioid use, more often following greater than
one month of use.Anaphylaxis: Anaphylaxis has been reported
with ingredients contained in DILAUDID Oral Solution or DILAUDID TabletsAndrogen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2).

7 Drug Interactions

Table 1 includes clinically
significant drug interactions with DILAUDID.Table 1: Clinically Significant Drug Interactions with DILAUDIDBenzodiazepines and other Central Nervous System
(CNS) DepressantsClinical Impact:Due to additive pharmacologic effect, the concomitant use of benzodiazepines
or other CNS depressants, including alcohol, can increase the risk
of hypotension, respiratory depression, profound sedation, coma, and
death.Intervention:Reserve concomitant prescribing of these drugs for use in patients
for whom alternative treatment options are inadequate. Limit dosages
and durations to the minimum required. Follow patients closely for
signs of respiratory depression and sedation [see Warnings
and Precautions (5.5)].Examples:Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers,
muscle relaxants, general anesthetics, antipsychotics, other opioids,
alcohol.Serotonergic DrugsClinical Impact:The concomitant use of opioids with other drugs that affect the
serotonergic neurotransmitter system has resulted in serotonin syndromeIntervention:If concomitant use is warranted, carefully observe the patient,
particularly during treatment initiation and dose adjustment. Discontinue
DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is
suspected.Examples:Selective serotonin reuptake inhibitors (SSRIs), serotonin and
norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants
(TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the
serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol),
monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric
disorders and also others, such as linezolid and intravenous methylene
blue).Monoamine Oxidase Inhibitors (MAOIs)Clinical Impact:MAOI interactions with opioids may manifest as serotonin syndrome
or opioid toxicity (e.g., respiratory depression, coma) [see
Warnings and Precautions (5.3)].If urgent use of an opioid is necessary, use test doses
and frequent titration of small doses to treat pain while closely
monitoring blood pressure and signs and symptoms of CNS and respiratory
depression.Intervention:The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended
for patients taking MAOIs or within 14 days of stopping such treatment.Examples:phenelzine, tranylcypromine, linezolidMixed Agonist/Antagonist and Partial Agonist
Opioid AnalgesicsClinical Impact:May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID
Tablets and/or precipitate withdrawal symptoms.Intervention:Avoid concomitant use.Examples:butorphanol, nalbuphine, pentazocine, buprenorphine,Muscle RelaxantsClinical Impact:Hydromorphone may enhance the neuromuscular blocking action of
skeletal muscle relaxants and produce an increased degree of respiratory
depression.Intervention:Monitor patients for signs of respiratory depression that may
be greater than otherwise expected and decrease the dosage of DILAUDID
Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary.DiureticsClinical Impact:Opioids can reduce the efficacy of diuretics by inducing the release
of antidiuretic hormone.Intervention:Monitor patients for signs of diminished diuresis and/or effects
on blood pressure and increase the dosage of the diuretic as needed.Anticholinergic DrugsClinical Impact:The concomitant use of anticholinergic drugs may increase risk
of urinary retention and/or severe constipation, which may lead to
paralytic ileus.Intervention:Monitor patients for signs of urinary retention or reduced gastric
motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly
with anticholinergic drugs.

8.1 Pregnancy

Risk SummaryProlonged use of opioid analgesics during
pregnancy may cause neonatal opioid withdrawal syndrome [see
Warnings and Precautions (5.4)]. There are no available data with DILAUDID in pregnant women to
inform a drug-associated risk for major birth defects and miscarriage.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.Clinical ConsiderationsFetal/Neonatal
Adverse ReactionsProlonged 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 (5.4)].Labor or DeliveryOpioids 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 Oral Solution or DILAUDID
Tablets 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 Oral Solution or DILAUDID Tablets,
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.DataAnimal DataPregnant 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 maternal toxicity.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.

8.2 Lactation

Risk SummaryLow 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 Oral Solution or DILAUDID Tablets
and any potential adverse effects on the breastfed infant from DILAUDID
Oral Solution or DILAUDID Tablets or from the underlying maternal
condition.Clinical ConsiderationsMonitor infants exposed to DILAUDID 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.

8.3 Females And Males Of Reproductive Potential

InfertilityChronic 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 (6.2), Clinical
Pharmacology (12.2), Nonclinical
Toxicology (13.1)].

8.4 Pediatric Use

The
safety and effectiveness of DILAUDID in pediatric patients have not
been established.

8.5 Geriatric Use

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
slowly in geriatric patients and montior closely for signs of central
nervous system and respiratory depression [see Warnings and
Precautions (5.6)].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.

8.6 Hepatic Impairment

The pharmacokinetics of hydromorphone is affected by hepatic impairment.
Due to increased exposure of hydromorphone, patients with 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 Pharmacology (12.3)].

8.7 Renal Impairment

The pharmacokinetics of hydromorphone is affected by renal impairment.
In addition, in patients with severe renal impairment, hydromorphone
appeared to be more slowly eliminated with a longer terminal elimination
half-life.  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 (12.3)].

9.1 Controlled Substance

DILAUDID Oral Solution and DILAUDID Tablets
contain hydromorphone, a Schedule II controlled substance.

9.2 Abuse

DILAUDID
Oral Solution and DILAUDID Tablets contain hydromorphone, a substance
with a high potential for abuse similar to other opioids including
fentanyl, hydrocodone, oxycodone, methadone, morphine, oxymorphone
and tapentadol. DILAUDID Oral Solution and DILAUDID Tablets can
be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)].All
patients treated with opioids require careful monitoring for signs
of abuse and addiction, because use of opioid analgesic products
carries the risk of addiction even under appropriate medical use.Prescription drug abuse is
the intentional non-therapeutic use of a prescription drug, even once,
for its rewarding psychological or physiological effects.Drug addiction is a cluster
of behavioral, cognitive, and physiological phenomena that develop
after repeated substance use and includes: a strong desire to take
the drug, difficulties in controlling its use, persisting in its use
despite harmful consequences, a higher priority given to drug use
than to other activities and obligations, increased tolerance, and
sometimes a physical withdrawal.“Drug-seeking” behavior is very common
in persons with substance use disorders. Drug-seeking tactics include
emergency calls or visits near the end of office hours, refusal to
undergo appropriate examination, testing, or referral, repeated “loss”
of prescriptions, tampering with prescriptions, and reluctance to
provide prior medical records or contact information for other treating
healthcare provider(s). “Doctor shopping” (visiting multiple prescribers
to obtain additional prescriptions) is common among drug abusers and
people suffering from untreated addiction. Preoccupation with achieving
adequate pain relief can be appropriate behavior in a patient with
poor pain control.Abuse and addiction are separate and distinct from physical dependence
and tolerance. Healthcare providers should be aware that addiction
may not be accompanied by concurrent tolerance and symptoms of physical
dependence in all addicts. In addition, abuse of opioids can occur
in the absence of true addiction.DILAUDID, like other opioids, can be diverted
for non-medical use into illicit channels of distribution. Careful
record-keeping of prescribing information, including quantity, frequency,
and renewal requests, as required by state and federal law, is strongly
advised.Proper assessment
of the patient, proper prescribing practices, periodic re-evaluation
of therapy, and proper dispensing and storage are appropriate measures
that help to limit abuse of opioid drugs.Risks Specific to Abuse of DILAUDIDDILAUDID Oral Solution
and DILAUDID Tablets are for oral use only. Abuse of DILAUDID Oral
Solution or DILAUDID Tablets poses a risk of overdose and death.
The risk is increased with concurrent abuse of DILAUDID ORAL LQIUID
or DILAUDID Tablets with alcohol and other central nervous system
depressants.Parenteral
drug abuse is commonly associated with transmission of infectious
diseases such as hepatitis and HIV.

9.3 Dependence

Both tolerance and physical dependence can develop during chronic
opioid therapy. Tolerance is the need for increasing doses of opioids
to maintain a defined effect such as analgesia (in the absence of
disease progression or other external factors). Tolerance may occur
to both the desired and undesired effects of drugs, and may develop
at different rates for different effects.Physical dependence results in withdrawal
symptoms after abrupt discontinuation or a significant dosage reduction
of a drug. Withdrawal also may be precipitated through the administration
of drugs with opioid antagonist activity (e.g., naloxone, nalmefene),
mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol,
nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence
may not occur to a clinically significant degree until after several
days to weeks of continued opioid usage.DILAUDID Oral Solution or DILAUDID Tablets
should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6)]. If DILAUDID Oral Solution or DILAUDID Tablets are abruptly
discontinued in a physically-dependent patient, a withdrawal syndrome
may occur. Some or all of the following can characterize this syndrome:
restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills,
myalgia, and mydriasis. Other signs and symptoms also may develop,
including irritability, anxiety, backache, joint pain, weakness, abdominal
cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased
blood pressure, respiratory rate, or heart rate.Infants born to mothers physically dependent
on opioids will also be physically dependent and may exhibit respiratory
difficulties and withdrawal signs [see Use in Specific Populations
(8.1)].

10 Overdosage

Clinical PresentationAcute overdose
with DILAUDID Oral Solution or DILAUDID Tablets can be manifested
by respiratory depression, somnolence progressing to stupor or coma,
skeletal muscle flaccidity, cold and clammy skin, constricted pupils,
and, in some cases, pulmonary edema, bradycardia, hypotension, partial
or complete airway obstruction, atypical snoring, and death. Marked
mydriasis rather than miosis may be seen with hypoxia in overdose
situations [see Clinical Pharmacology (12.2)].Treatment of OverdoseIn case of overdose,
priorities are the reestablishment of a patent and protected airway
and institution of assisted or controlled ventilation, if needed.
Employ other supportive measures (including oxygen and vasopressors)
in the management of circulatory shock and pulmonary edema as indicated.
Cardiac arrest or arrhythmias will require advanced life-support techniques.The opioid antagonists, naloxone
or nalmefene, are specific antidotes to respiratory depression resulting
from opioid overdose. For clinically significant respiratory or circulatory
depression secondary to hydromorphone overdose, administer an opioid
antagonist. Opioid antagonists should not be administered in the
absence of clinically significant respiratory or circulatory depression
secondary to hydromorphone overdose.Because the duration of opioid reversal
is expected to be less than the duration of action of hydromorphone
in DILAUDID Oral Solution or DILAUDID Tablets, carefully monitor the
patient until spontaneous respiration is reliably reestablished. If
the response to an opioid antagonist is suboptimal or only brief in
nature, administer additional antagonist as directed by the product’s
prescribing information.In an individual physically dependent on
opioids, administration of the recommended usual dosage of the antagonist
will precipitate an acute withdrawal syndrome. The severity of the
withdrawal symptoms experienced will depend on the degree of physical
dependence and the dose of the antagonist administered. If a decision
is made to treat serious respiratory depression in the physically
dependent patient, administration of the antagonist should be initiated
with care and by titration with smaller than usual doses of the antagonist.

11 Description

DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of
morphine, is an opioid agonist.DILAUDID Tablets are supplied in 2 mg,
4 mg, and 8 mg tablets for oral administration. The tablet strengths
describe the amount of hydromorphone hydrochloride in each tablet.DILAUDID Oral Solution is supplied
as 5mg/ 5 mL (1 mg/mL) viscous liquid.The chemical name is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one
hydrochloride. The molecular Weight is 321.80. Its molecular formula
is C17H19NO3·HCl, and it has the following chemical structure:Hydromorphone hydrochloride
is a white or almost white crystalline powder that is freely soluble
in water, very slightly soluble in ethanol (96%), and practically
insoluble in methylene chloride.The 2 mg, 4 mg, and 8 mg tablets contain
the following inactive ingredients: lactose anhydrous and magnesium
stearate. DILAUDID Tablets may also contain traces of sodium metabisulfite.The 2 mg tablets also contain
D&C red #30 Lake dye, and D&C yellow #10 Lake dye.The 4 mg tablets also contain
D&C yellow #10 Lake dye.Each 5 mL (1 teaspoon) of DILAUDID Oral
Solution contains 5 mg of hydromorphone hydrochloride. The inactive
ingredients are purified water, methylparaben, propylparaben, sucrose,
and glycerin. DILAUDID Oral Solution may contain traces of sodium
metabisulfite.

12.1 Mechanism Of Action

Hydromorphone is a full opioid agonist and is relatively selective
for the mu-opioid receptor, although it can bind to other opioid receptors
at higher doses. The principal therapeutic action of hydromorphone
is analgesia. Like all full opioid agonists, there is no ceiling
effect for analgesia with morphine. Clinically, dosage is titrated
to provide adequate analgesia and may be limited by adverse reactions,
including respiratory and CNS depression.The precise mechanism of the analgesic
action is unknown. However, specific CNS opioid receptors for endogenous
compounds with opioid-like activity have been identified throughout
the brain and spinal cord and are thought to play a role in the analgesic
effects of this drug.

12.2 Pharmacodynamics

Effects on the Central Nervous
SystemHydromorphone produces respiratory depression by direct action on
brain stem respiratory centers. The respiratory depression involves
a reduction in the responsiveness of the brain stem respiratory centers
to both increases in carbon dioxide tension and to electrical stimulation.Hydromorphone causes miosis,
even in total darkness. Pinpoint pupils are a sign of opioid overdose
but are not pathognomonic (e.g., pontine lesions of hemorrhagic or
ischemic origins may produce similar findings). Marked mydriasis rather
than miosis may be seen due to hypoxia in overdose situations.Effects on the Gastrointestinal
Tract and Other Smooth MuscleHydromorphone causes a reduction in motility
associated with an increase in smooth muscle tone in the antrum of
the stomach and duodenum. Digestion of food in the small intestine
is delayed and propulsive contractions are decreased. Propulsive peristaltic
waves in the colon are decreased, while tone may be increased to the
point of spasm, resulting in constipation. Other opioid-induced effects
may include a reduction in biliary and pancreatic secretions, spasm
of sphincter of Oddi, and transient elevations in serum amylase.Effects on the
Cardiovascular SystemHydromorphone produces peripheral vasodilation
which may result in orthostatic hypotension or syncope. Manifestations
of histamine release and/or peripheral vasodilation may include pruritus,
flushing, red eyes and sweating and/or orthostatic hypotension.Effects on the
Endocrine SystemOpioids inhibit the secretion of adrenocorticotropic
hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans[see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and
pancreatic secretion of insulin and glucagon.Chronic use of opioids may influence the
hypothalamic-pituitary-gonadal axis, leading to androgen deficiency
that may manifest as low libido, impotence, erectile dysfunction,
amenorrhea, or infertility. The causal role of opioids in the clinical
syndrome of hypogonadism is unknown because the various medical,
physical, lifestyle, and psychological stressors that may influence
gonadal hormone levels have not been adequately controlled for in
studies conducted to date [see Adverse Reactions (6.2)].Effects on the Immune SystemOpioids have been
shown to have a variety of effects on components of the immune system
in in vitro and animal models. The clinical significance of these
findings is unknown. Overall, the effects of opioids appear to be
modestly immunosuppressive.Concentration–Efficacy RelationshipsThe minimum effective
analgesic concentration will vary widely among patients, especially
among patients who have been previously treated with potent agonist
opioids. The minimum effective analgesic concentration of hydromorphone
for any individual patient may increase over time due to an increase
in pain, the development of a new pain syndrome, and/or the development
of analgesic tolerance[see Dosage and Administration (2.1, 2.5)].Concentration–Adverse Reaction RelationshipsThere is a relationship between
increasing hydromorphone plasma concentration and increasing frequency
of dose-related opioid adverse reactions such as nausea, vomiting,
CNS effects, and respiratory depression. In opioid-tolerant patients,
the situation may be altered by the development of tolerance to opioid-related
adverse reactions [see Dosage and Administration (2.2, 2.3, 2.5)].

12.3 Pharmacokinetics

AbsorptionThe analgesic activity of DILAUDID
(hydromorphone hydrochloride) is due to the parent drug, hydromorphone.
Hydromorphone is rapidly absorbed from the gastrointestinal tract
after oral administration and undergoes extensive first-pass metabolism.
Exposure of hydromorphone (Cmax and AUC0-24) is dose-proportional at a dose range of 2 and 8
mg. In vivo bioavailability following single-dose
administration of the 8 mg tablet is approximately 24% (coefficient
of variation 21%). Bioequivalence between the DILAUDID 8 mg TABLET
and an equivalent dose of DILAUDID Oral Solution has been demonstrated.After oral administration of
DILAUDID, peak plasma hydromorphone concentrations are generally attained
within ½ to 1-hour.Mean (%cv)Dosage FormCmax(ng)Tmax(hrs)AUC(ng*hr/mL)T½(hrs)8 mg Tablet5.5 (33%)0.74 (34%)23.7 (28%)2.6 (18%)8 mg Oral Liquid5.7 (31%)0.73 (71%)24.6 (29%)2.8 (20%)Food EffectsIn a study conducted
with a single 8 mg dose of hydromorphone (2 mg hydromorphone immediate-release
tablets), food lowered Cmax by 25%, prolonged
Tmax by 0.8 hour, and increased AUC by 35%. The effects may not be
clinically relevant.DistributionAt therapeutic plasma levels, hydromorphone
is approximately 8-19% bound to plasma proteins. After an intravenous
bolus dose, the steady state of volume distribution [mean (% cv)]
is 302.9 (32%) liters.EliminationThe systemic clearance is approximately
1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone
after an intravenous dose is about 2.3 hours.MetabolismHydromorphone is extensively
metabolized via glucuronidation in the liver, with greater than 95%
of the dose metabolized to hydromorphone-3-glucuronide along with
minor amounts of 6-hydroxy reduction metabolites.ExcretionOnly a small amount of the hydromorphone
dose is excreted unchanged in the urine. Most of the dose is excreted
as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy
reduction metabolites.Specific PopulationsHepatic ImpairmentAfter oral administration of
a single 4 mg dose (2 mg hydromorphone immediate-release tablets),
mean exposure to hydromorphone (Cmax and AUC∞)
is increased 4-fold in patients with moderate (Child-Pugh Group B)
hepatic impairment compared with subjects with normal hepatic function.
Due to increased exposure of hydromorphone, patients with moderate
hepatic impairment should be started at a lower dose and closely monitored
during dose titration. Pharmacokinetics of hydromorphone in severe
hepatic impairment patients has not been studied. Further increase
in Cmax and AUC of hydromorphone in this group
is expected. As such, starting dose should be even more conservative [see Use in Specific Populations (8.6)].Renal ImpairmentAfter oral administration of a single 4
mg dose (2 mg hydromorphone immediate-release tablets), exposure to
hydromorphone ( Cmax and AUC0-48) is increased
in patients with impaired renal function by 2-fold in moderate (CLcr
= 40 - 60 mL/min) and 3-fold in severe (CLcr < 30 mL/min) renal
impairment compared with normal subjects (CLcr > 80 mL/min). In addition,
in patients with severe renal impairment hydromorphone appeared to
be more slowly eliminated with longer terminal elimination half-life
(40 hr) compared to patients with normal renal function (15 hr). Patients
with moderate renal impairment should be started on a lower dose.
Starting doses for patients with severe renal impairment should be
even lower. Patients with renal impairment should be closely monitored
during dose titration [see Use in Specific Populations (8.7)].Age: Geriatric PopulationIn the geriatric
population, age has no effect on the pharmacokinetics of hydromorphone.SexSex has little effect on the
pharmacokinetics of hydromorphone. Females appear to have higher Cmax (25%) than males with comparable AUC0-24 values.
The difference observed in Cmax may not be
clinically relevant.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisLong term studies in animals
to evaluate the carcinogenic potential of hydromorphone have not been
conducted.MutagenesisHydromorphone 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 FertilityReduced 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.

14 Clinical Studies

Analgesic effects of single
doses of DILAUDID Oral Solution administered to patients with post-surgical
pain have been studied in double-blind controlled trials. In one study,
both 5 mg and 10 mg of DILAUDID Oral Solution provided significantly
more analgesia than placebo. In another trial, 5 mg and 10 mg of DILAUDID
Oral Solution were compared to 30 mg and 60 mg of morphine sulfate
oral liquid. The pain relief provided by 5 mg and 10 mg DILAUDID Oral
Solution was comparable to 30 mg and 60 mg oral morphine sulfate,
respectively.

16 How Supplied/Storage And Handling

Protect from light.DILAUDID Oral Solution is a a clear, colorless to pale yellow, slightly
viscous liquid. It is available in: Bottles of 1 pint (473 mL) – NDC#
59011-451-01.DILAUDID
2 mg Tablets are light orange, round, flat-faced tablets, with beveled
edges, debossed with a “P” on one side and the number “2” on the opposite
side. They are available in:Bottles of 100 - NDC # 59011-452-10Unit Dose Packages of 100 (4x25) - NDC # 59011-452-01DILAUDID 4 mg Tablets are light
yellow, round, flat-faced tablets, with beveled edges, debossed with
a “P” on one side and the number “4” on the opposite side. They are
available in:Bottles of 100 - NDC # 59011-454-10Unit Dose Packages of 100 (4x25) - NDC # 59011-454-01Bottles of 500 - NDC # 59011-454-05DILAUDID 8 mg Tablets are white, triangular
shaped tablets debossed with a “P” and an inverted “P” separated with
a bisect on one side of the tablet and debossed with the number “8”
on the other side of the tablet. They are available in:Bottles of 100 - NDC# 59011-458-10Store at 25°C (77°F); excursions permitted
to 15°-30°C (59°-86°F). [See USP Controlled Room Temperature].

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication
  • Guide).Medication ErrorsInstruct patients how to measure and take
  • The correct dose of DILAUDID, and to always use the enclosed cup when
  • Administering DILAUDID Oral Solution to ensure the dose is measured
  • And administered accurately [see Warnings and Precautions
  • (5.1)].If the prescribed concentration is changed,
  • Instruct patients on how to correctly measure the new dose to avoid
  • Errors which could result in accidental overdose and death.Addiction, Abuse,
  • And MisuseInform patients that the use of DILAUDID Oral Solution or DILAUDUD
  • Tablets, even when taken as recommended, can result in addiction,
  • Abuse, and misuse, which can lead to overdose and death [see
  • Warnings and Precautions (5.2)]. Instruct patients not to share DILAUDID Oral Solution or DILAUDUD
  • Tablets with others and to take steps to protect DILAUDID Oral Solution
  • Or DILAUDUD Tablets from theft or misuse.Life-Threatening Respiratory
  • DepressionInform patients of the risk of life-threatening respiratory depression,
  • Including information that the risk is greatest when starting DILAUDID
  • Oral Solution or DILAUDUD Tablets or when the dosage is increased,
  • And that it can occur even at recommended dosages [see Warnings
  • And Precautions (5.3)].
  • Advise patients how to recognize respiratory depression and to seek
  • Medical attention if breathing difficulties develop.Accidental IngestionInform patients
  • That accidental ingestion, especially by children, may result in respiratory
  • Depression or death [see Warnings and Precautions (5.3)]. Instruct patients to take
  • Steps to store DILAUDID Oral Solution or DILAUDUD Tablets securely
  • And to dispose of unused DILAUDID Oral Solution or DILAUDUD Tablets.
  • When DILAUDID Oral Solution or DILAUDUD Tablets are no longer needed,
  • The unused medication should be destroyed by flushing it down the
  • Toilet.Interactions with Benzodiazepines and Other CNS DepressantsInform patients
  • And caregivers that potentially fatal additive effects may occur if
  • DILAUDID Oral Solution or DILAUDUD Tablets are used with benzodiazepines
  • Or other CNS depressants, including alcohol, and not to use these
  • Concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.4), Drug Interactions (7)].Serotonin
  • SyndromeInform patients that DILAUDID 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 medications. [see Drug
  • Interactions 7].MAOI InteractionInform patients
  • To avoid taking DILAUDID Oral Solution or DILAUDUD Tablets while using
  • Any drugs that inhibit monoamine oxidase. Patients should not start
  • MAOIs while taking DILAUDID Oral Solution or DILAUDUD Tablets [see Dug Interactions (7)].Adrenal
  • InsufficiencyInform 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 (5.7)].Important Administration
  • InstructionsInstruct patients how to properly take
  • DILAUDID.Advise patients to always obtain a calibrated oral syringe/dosing
  • Cup from the pharmacist for administering DILAUDID Oral Solution to
  • Ensure that the dose is measured and administered accurately [see Warnings and Precautions (5.1)]. Advise patients never to use household teaspoons or
  • Tablespoons to measure DILAUDID Oral Solution.Advise patients not to adjust the dose of DILAUDID Oral
  • Solution or DILAUDID Tablets without consulting with a physician or
  • Other healthcare professional.If patients have been receiving treatment with DILAUDID
  • Oral Solution or DILAUDID Tablets for more than a few weeks and cessation
  • Of therapy is indicated, counsel them on the importance of safely
  • Tapering the dose as abrupt discontinuation of the medication could
  • Precipitate withdrawal symptoms. Provide a dose schedule to accomplish
  • A gradual discontinuation of the medication [see Dosage and
  • Administration (2.5, 2.6)].HypotensionInform patients
  • That DILAUDID Oral Solution or DILAUDID Tablets 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
  • (5.8)].AnaphylaxisInform patients that anaphylaxis
  • Has been reported with ingredients contained in DILAUDID Oral Solution
  • Or DILAUDID Tablets. Advise patients how to recognize such a reaction
  • And when to seek medical attention [see Contraindications
  • (4), Adverse Reactions (6)].PregnancyNeonatal Opioid Withdrawal
  • SyndromeInform female patients of reproductive
  • Potential that prolonged use of DILAUDID Oral Solution or DILAUDID
  • Tablets during pregnancy can result in neonatal opioid withdrawal
  • Syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].Embryo-Fetal ToxicityInform female patients
  • Of reproductive potential that DILAUDID Oral Solution or DILAUDID
  • Tablets can cause fetal harm and to inform their healthcare provider
  • Of a known or suspected pregnancy [see Use in Specific Populations
  • (8.1), Warnings and Precautions (5.4)]LactationAdvise 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
  • (8.2)].InfertilityInform 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
  • Population (8.3)].Driving or Operating
  • Heavy MachineryInform patients that DILAUDID Oral Solution
  • Or DILAUDID Tablets 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 [see Warnings and Precautions
  • (5.13)].ConstipationAdvise patients of the potential
  • For severe constipation, including management instructions and when
  • To seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].Disposal of Unused DILAUDID Oral Solution or DILAUDID Tablets Advise patients to flush unused
  • DILAUDID Oral Solution or DILAUDID Tablets down the toilet.Healthcare professionals can
  • Telephone Purdue Pharma L.P.’s Medical Services Department (1-888-726-7535)
  • For information on this product.Manufactured for Purdue Pharma L.P. Stamford,
  • CT 06901-3431By
  • Halo Pharmaceutical, Inc. Whippany, NJ 07981Revised: 12/2016

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