Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

DILAUDID (NDA-019891)

(HYDROMORPHONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/15/2023 (SUPPL-31)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

…

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use of DILAUDID Oral Solution and DILAUDID Tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of DILAUDID Oral Solution and DILAUDID Tablets are essential [see Warnings and Precautions (5.3)].

…

5 Warnings and Precautions

5.1 Risk of Accidental Overdose and Death due to Medication Errors

Additions and/or revisions underlined:

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with other hydromorphone oral solutions of different concentrations, when prescribing, dispensing, and administering DILAUDID Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately.

Instruct patients and caregivers on how to measure and take or administer the correct dose of DILAUDID Oral Solution and to use extreme caution when measuring the dose. Strongly advise patients and caregivers to obtain and always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not accurate measuring devices.

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

…

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. 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 careful storage of the drug during the course of treatment and the proper disposal of unused drug. 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.

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… Inform patients and caregivers of this potential interaction and educate then on the signs and symptoms of respiratory depression (including sedation).

…

5.7 Opioid-Induced Hyperalgesia and Allodynia

New subsection added:

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)].

Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.7), Warnings and Precautions (5.14)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

Use of opioids for an extended period of time 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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Medication Errors

Instruct patients and caregivers how to measure and take or administer the correct dose of DILAUDID Oral Solution, and to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication. Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure DILAUDID Oral Solution [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].

If the prescribed concentration is changed, instruct patients and caregivers on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.

…

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7), Adverse Reactions (6.2)].

…

Important Administration Instructions

Instruct patients how to properly take DILAUDID [see Dosage and Administration (2), Warnings and Precautions (5.1)].

Instruct patients and caregivers on how to accurately measure and take the correct dose of DILAUDID Oral Solution.
Strongly advise patients and caregivers to always use a graduated oral dosing syringe or measuring cup with metric units of measurements (i.e., mL) to correctly measure the prescribed amount of medication.
Inform patients and caregivers that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure DILAUDID Oral Solution [see Dosage and Administration (2)].
Advise patients and caregivers not to adjust the dose of DILAUDID Oral Solution without consulting with a physician or other healthcare professional.

…

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Population (8.3)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Tell your healthcare provider if you are:

Noticing your pain getting worse. If your pain gets worse after you take DILAUDID, do not take more of DILAUDID without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking DILAUDID.
…
When taking DILAUDID:
…

For acute (short-term) pain, you may only need to take DILAUDID for a few days. You may have some DILAUDID left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused DILAUDID.
…

03/04/2021 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:

… 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 or DILAUDID Tablets along with intensive monitoring for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

5.4 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

… Accidental ingestion of even one dose of DILAUDID Oral Solution and DILAUDID Tablets, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.7)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with DILAUDID Oral Solution and DILAUDID Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)].

5.6 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… 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.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with DILAUDID Oral Solution or DILAUDID Tablets

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.4, 5.6)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.4, 5.6)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Important information about DILAUDID Oral Solution and DILAUDID Tablets:

Additions and/or revisions underlined:

Get emergency help or call 911 right away if you take too much DILAUDID Tablets or DILAUDID Oral Solution (overdose). When you first start taking DILAUDID Oral Solution or DILAUDID Tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.

Before taking DILAUDID Oral Solution or DILAUDID Tablets, tell your healthcare provider if you have a history of:

abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.

Tell your healthcare provider if you are:

living in a household where there are small children or someone who has abused street or prescription drugs

Get emergency medical help or call 911 right away if you have: …

PATIENT COUNSELING INFORMATION

Life-Threatening Respiratory Depression

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with DILAUDID Oral Solution and DILAUDID Tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administrations (2.2), Warnings and Precautions (5.4)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

How to treat with naloxone in the event of an opioid overdose
To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Life-Threatening Respiratory Depression

Newly added information to end of subsection:

Additions and/or revisions underlined:

5.13 Withdrawal

Do not abruptly discontinue DILAUDID ORAL SOLUTION OR DILAUDID TABLETS in a patient physically dependent on opioids. When discontinuing DILAUDID Oral Solution or DILAUDID Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of hydromorphone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.

Additionally, avoid the use of mixed agonist/antagonist …

7 Drug Interactions

Table 1: Clinically Significant Drug Interactions with DILAUDID Oral Solution or DILAUDID Tablets

Serotonergic Drugs

Additions and/or revisions underlined:

Example: 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), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

Important information about DILAUDID:

Store DILAUDID ORAL SOLUTION OR DILAUDID TABLETS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

When taking DILAUDID:

Dispose of expired, unwanted, or unused DILAUDID ORAL SOLUTION OR DILAUDID TABLETS by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store DILAUDID ORAL SOLUTION OR DILAUDID TABLETS securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving DILAUDID ORAL SOLUTION OR DILAUDID TABLETS unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused DILAUDID ORAL SOLUTION OR DILAUDID TABLETS should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Newly added titled section:

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue DILAUDID ORAL SOLUTION OR DILAUDID TABLETS without first discussing a tapering plan with the prescriber.

09/18/2018 (SUPPL-27)

Approved Drug Label (PDF)

Boxed Warning

In the boxed warning title, the following underlined language was added after “ADDICTION, ABUSE, AND MISUSE”: RISK EVALUATION AND MITIGATION STRATEGY (REMS)

Addition of the following information:

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to

complete a REMS-compliant education program,
counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
consider other tools to improve patient, household, and community safety.

5 Warnings and Precautions

Addition of the following subsection after the warning regarding addiction, abuse and misuse:

5.3 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503- 0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

12/16/2016 (SUPPL-24)

Approved Drug Label (PDF)

Boxed Warning

(section added)

WARNING: RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Risk of Medication Errors

Ensure 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.

Addiction, Abuse, and Misuse

DILAUDID 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.

Life-Threatening Respiratory Depression

Serious, 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.

Accidental Ingestion

Accidental ingestion of even one dose of DILAUDID Oral Solution or DILAUDID Tablets, especially by children, can result in a fatal overdose of hydromorphone.

Neonatal Opioid Withdrawal Syndrome

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, 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.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

• 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.

4 Contraindications

(additions underlined)

DILAUDID Oral Solution and DILAUDID Tablets are contraindicated in patients with:

• Significant respiratory depression

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

• Known or suspected gastrointestinal obstruction, including paralytic ileus

• Hypersensitivity to hydromorphone, hydromorphone salts, any other components of the product, or sulfite-containing medications (e.g., anaphylaxis)

5 Warnings and Precautions

5.1 Risk of Accidental Overdose and Death due to Medication Errors

(subsection added)

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.

5.10 Risks of Use in Patients with Gastrointestinal Conditions

(subsection added)

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

(subsection added)

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 occurring 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

(additions underlined)

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.

When discontinuing DILAUDID Oral Solution or DILAUDID Tablets in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue DILAUDID Oral Solution or DILAUDID Tablets in these patients.

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.

5.2 Addiction, Abuse, and Misuse

(additions underlined)

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.

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. 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

(subsection added)

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 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

(subsection revised, additions underlined)

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.

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

(subsection added)

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.

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.

5.6 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

(subsection added)

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.

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.

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. Alternatively, consider the use of non-opioid analgesics in these patients.

5.7 Adrenal Insufficiency

(subsection added)

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

(additions underlined)

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). 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

(additions underlined)

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.

6 Adverse Reactions

6.1 Clinical Trial Experience

(subsection added, please refer to label)

6.2 Postmarketing Experience

(Subsection added)

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 Tablets

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids

(additions underlined)

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse

• Life-Threatening Respiratory Depression

• Neonatal Opioid Withdrawal Syndrome

• Interactions with Benzodiazepines or Other CNS Depressants

• Adrenal Insufficiency

• Severe Hypotension

• Gastrointestinal Adverse Reactions

• Seizures

• Withdrawal

7 Drug Interactions

(Extensive additions, please refer to Table 1 in label)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

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 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 Considerations

Monitor 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

(PLLR conversion)

Infertility

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.

8.5 Geriatric Use

(additions underlined)

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 monitor closely for signs of central nervous system and respiratory depression.

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

(additions underlined)

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 astarting dose.

8.7 Renal Impairment

(additions underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Extensive additions, please refer to label)

Medication Guide

(Newly added, please refer to label)

Other

Revisions to the Package Insert to incorporate the opioid analgesic template language

Physicians Labeling Rule (PLR) conversion