Hydromorphone Hydrochloride

Hydromorphone hydrochloride extended-release tablets are indicated for the management of severe and persistent pain that requires an opioid analgesic and that cannot be adequately treated with alternative options, including immediate-release opioids.

Patients considered opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

• •Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy,
  [see Warnings and Precautions (

  5.1 Addiction, Abuse, and Misuse

  Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience ]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and reassess all patients receiving hydromorphone hydrochloride extended-release 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions (

  5.2

  )]

  .

  Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release 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 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.

  )]
  , reserve opioid analgesics, including hydromorphone hydrochloride extended-release tablets, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• •Hydromorphone hydrochloride extended-release tablets are not indicated as an as-needed (prn) analgesic.

• •Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks. (
  2.1 Important Dosage and Administration Information

  To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

  Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablet therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

  Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
    [see Warnings and Precautions ]
    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • •Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
    [see Warnings and Precautions ]
    .
  • •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments
    [see Warnings and Precautions ]
    .

  Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole

  [see Patient Counseling Information ]

  . Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death

  [see Warnings and Precautions ]

  .
  )
• •For once daily administration IN OPIOID-TOLERANT PATIENTS. (
  2.1 Important Dosage and Administration Information

  To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

  Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablet therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

  Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
    [see Warnings and Precautions ]
    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • •Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
    [see Warnings and Precautions ]
    .
  • •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments
    [see Warnings and Precautions ]
    .

  Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole

  [see Patient Counseling Information ]

  . Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death

  [see Warnings and Precautions ]

  .
  )
• •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (
  2.1 Important Dosage and Administration Information

  To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

  Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablet therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

  Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
    [see Warnings and Precautions ]
    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • •Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
    [see Warnings and Precautions ]
    .
  • •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments
    [see Warnings and Precautions ]
    .

  Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole

  [see Patient Counseling Information ]

  . Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death

  [see Warnings and Precautions ]

  .
  ,
  5 WARNINGS AND PRECAUTIONS

  • •
    Opioid Induced Hyperalgesia (OIH) and Allodynia
    : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation.
  • •
    Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or Elderly Cachectic Debilitated Patients
    : Regularly evaluate, particularly during initiation and titration.
  • •
    Adrenal Insufficiency
    : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
  • •
    Severe Hypotension
    : Regularly evaluate during dose initiation and titration. Avoid use of hydromorphone hydrochloride extended-release tablets in patients with circulatory shock.
  • •
    Risks of Use in Patients with Increased Intracranial Pressure, Brain, Tumors, Head Injury, or Impaired Consciousness
    : Monitor for sedation and respiratory depression. Avoid use of hydromorphone hydrochloride extended-release tablets in patients with impaired consciousness or coma.

  5.1 Addiction, Abuse, and Misuse

  Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience ]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and reassess all patients receiving hydromorphone hydrochloride extended-release 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions (

  5.2

  )]

  .

  Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release 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 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.

  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydromorphone hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential

  [see Dosage and Administration ]

  . Overestimating the hydromorphone hydrochloride extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose.

  Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release 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 ]

  .

  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 (

  2.5

  )]

  .

  Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions ]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydromorphone hydrochloride extended-release tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, and other opioids). 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 ]

  .

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

  If concomitant use is warranted, consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when hydromorphone hydrochloride extended-release 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 , Patient Counseling Information ]

  .

  5.4 Neonatal Opioid Withdrawal Syndrome

  Use of hydromorphone hydrochloride extended-release tablets for an extended period of time 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 an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

  [see Use in Specific Populations , Patient Counseling Information ]

  .

  5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

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

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

  5.6 Opioid-Induced Hyperalgesia and Allodynia

  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 ]

  . 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 ; Warnings and Precautions ]

  .

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

  The use of hydromorphone hydrochloride extended-release 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

  :

  Hydromorphone hydrochloride extended-release tablets 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 hydromorphone hydrochloride extended-release tablets

  [see Warnings and Precautions (

  5.2

  )]

  .

  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 (

  5.2

  )]

  .

  Regularly evaluate such patients closely, particularly when initiating and titrating hydromorphone hydrochloride extended-release tablets and when hydromorphone hydrochloride extended-release tablets are given concomitantly with other drugs that depress respiration

  [see Warnings and Precautions , Drug Interactions ]

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

  5.8 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.

  5.9 Severe Hypotension

  Hydromorphone hydrochloride extended-release tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an 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 ]

  . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of hydromorphone hydrochloride extended-release tablets. In patients with circulatory shock, hydromorphone hydrochloride extended-release tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of hydromorphone hydrochloride extended-release tablets in patients with circulatory shock.

  5.10 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 CO₂retention (e.g., those with evidence of increased intracranial pressure or brain tumors), hydromorphone hydrochloride extended-release tablets may reduce respiratory drive, and the resultant CO₂retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with hydromorphone hydrochloride extended-release tablets.

  Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of hydromorphone hydrochloride extended-release tablets in patients with impaired consciousness or coma.

  5.11 Risks of Gastrointestinal Complications

  Hydromorphone hydrochloride extended-release tablets are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Avoid the use of hydromorphone hydrochloride extended-release tablets in patients with other GI obstruction.

  Because the shell of the hydromorphone hydrochloride extended-release tablet is insoluble, it may remain intact during gastrointestinal transit and be eliminated in the feces. Hydromorphone hydrochloride extended-release tablets are contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

  It is possible that hydromorphone hydrochloride extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

  The hydromorphone in hydromorphone hydrochloride extended-release tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

  Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate.

  5.12 Increased Risk of Seizures in Patients with Seizure Disorders

  The hydromorphone in hydromorphone hydrochloride extended-release 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. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during hydromorphone hydrochloride extended-release tablet therapy.

  5.13 Withdrawal

  Do not abruptly discontinue hydromorphone hydrochloride extended-release tablets in a patient physically dependent on opioids. When discontinuing hydromorphone hydrochloride extended-release 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

  [see Dosage and Administration (

  2.5

  ), Drug Abuse and Dependence ]

  .

  Additionally, 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 hydromorphone hydrochloride extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms

  [see Drug Interactions ]

  .

  5.14 Sulfites

  Hydromorphone hydrochloride extended-release 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

  [see Adverse Reactions ]

  .

  5.15 Risks of Driving and Operating Machinery

  Hydromorphone hydrochloride extended-release tablets may impair the mental and/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 hydromorphone hydrochloride extended-release tablets and know how they will react to the medication

  [see Patient Counseling Information ]

  .
  )
• •Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse (
  5.1 Addiction, Abuse, and Misuse

  Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience ]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and reassess all patients receiving hydromorphone hydrochloride extended-release 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions (

  5.2

  )]

  .

  Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release 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 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.
  )
• •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments (
  2.1 Important Dosage and Administration Information

  To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

  Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablet therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

  Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
    [see Warnings and Precautions ]
    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • •Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
    [see Warnings and Precautions ]
    .
  • •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments
    [see Warnings and Precautions ]
    .

  Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole

  [see Patient Counseling Information ]

  . Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death

  [see Warnings and Precautions ]

  .
  ,
  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydromorphone hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential

  [see Dosage and Administration ]

  . Overestimating the hydromorphone hydrochloride extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose.

  Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release 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 ]

  .

  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 (

  2.5

  )]

  .

  Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions ]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .
  )
• •Instruct patients to swallow hydromorphone hydrochloride extended-release tablets intact, and not to cut, break, chew, crush, or dissolve the tablets (risk of potentially fatal overdose). (
  2.1 Important Dosage and Administration Information

  To avoid medication errors, prescribers and pharmacists must be aware that hydromorphone is available as both immediate-release 8 mg tablets and extended-release 8 mg tablets.

  Hydromorphone hydrochloride extended-release tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of extended-release/long-acting opioids and how to mitigate the associated risks.

  Due to the risk of respiratory depression, hydromorphone hydrochloride extended-release tablets are only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning hydromorphone hydrochloride extended-release tablet therapy. As hydromorphone hydrochloride extended-release tablets are only for use in opioid-tolerant patients, do not begin any patient on hydromorphone hydrochloride extended-release tablets as the first opioid.

  Patients who are opioid-tolerant are those receiving, for one week or longer, at least 60 mg of oral morphine per day, at least 25 mcg transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

  • •Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals
    [see Warnings and Precautions ]
    . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of hydromorphone hydrochloride extended-release tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
  • •Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse
    [see Warnings and Precautions ]
    .
  • •Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with hydromorphone hydrochloride extended-release tablets. Consider this risk when selecting an initial dose and when making dose adjustments
    [see Warnings and Precautions ]
    .

  Instruct patients to swallow hydromorphone hydrochloride extended-release tablets whole

  [see Patient Counseling Information ]

  . Crushing, chewing, or dissolving hydromorphone hydrochloride extended-release tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death

  [see Warnings and Precautions ]

  .
  ,
  5.1 Addiction, Abuse, and Misuse

  Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience ]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and reassess all patients receiving hydromorphone hydrochloride extended-release 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions (

  5.2

  )]

  .

  Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release 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 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.
  )
• •Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with hydromorphone hydrochloride extended-release tablets, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. (
  2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions ]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program)

  [see Warnings and Precautions ]

  .

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.
  ,
  5.1 Addiction, Abuse, and Misuse

  Hydromorphone hydrochloride extended-release tablets contain hydromorphone, a Schedule II controlled substance. As an opioid, hydromorphone hydrochloride extended-release tablets expose users to the risks of addiction, abuse, and misuse

  [see Drug Abuse and Dependence ]

  .

  Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed hydromorphone hydrochloride extended-release tablets and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use

  [see Postmarketing Experience ]

  .

  Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing hydromorphone hydrochloride extended-release tablets, and reassess all patients receiving hydromorphone hydrochloride extended-release 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 addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of hydromorphone hydrochloride extended-release tablets for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as hydromorphone hydrochloride extended-release tablets, but use in such patients necessitates intensive counseling about the risks and proper use of hydromorphone hydrochloride extended-release tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions (

  5.2

  )]

  .

  Abuse or misuse of hydromorphone hydrochloride extended-release tablets by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death

  [see Overdosage ]

  .

  Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing hydromorphone hydrochloride extended-release 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 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.
  ,
  5.2 Life-Threatening Respiratory Depression

  Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status

  [see Overdosage ]

  . Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of hydromorphone hydrochloride extended-release tablets, the risk is greatest during the initiation of therapy or following a dosage increase.

  To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone hydrochloride extended-release tablets are essential

  [see Dosage and Administration ]

  . Overestimating the hydromorphone hydrochloride extended-release tablets dose when converting patients from another opioid product can result in fatal overdose with the first dose.

  Accidental ingestion of even one dose of hydromorphone hydrochloride extended-release 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 ]

  .

  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 (

  2.5

  )]

  .

  Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

  Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient

  [see Warnings and Precautions ]

  .

  Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

  There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

  Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .
  ,
  5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

  Profound sedation, respiratory depression, coma, and death may result from the concomitant use of hydromorphone hydrochloride extended-release tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, and other opioids). 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 ]

  .

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

  If concomitant use is warranted, consider prescribing an opioid overdose reversal agent

  [see Dosage and Administration , Warnings and Precautions , Overdosage ]

  .

  Advise both patients and caregivers about the risks of respiratory depression and sedation when hydromorphone hydrochloride extended-release 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 , Patient Counseling Information ]

  .
  )
• •Dose may be increased using increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia. (
  2.4 Titration and Maintenance of Therapy

  Individually titrate hydromorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydromorphone hydrochloride extended-release tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . 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. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  Plasma levels of hydromorphone hydrochloride extended-release tablets are sustained for 18 to 24 hours. Dosage adjustments of hydromorphone hydrochloride extended-release tablets may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.

  Patients who experience breakthrough pain may require a dose increase of hydromorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the hydromorphone hydrochloride extended-release tablets dose.

  If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage

  [see Warnings and Precautions ]

  . Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
  )
• •Periodically reassess patients receiving hydromorphone hydrochloride extended-release tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (
  2.4 Titration and Maintenance of Therapy

  Individually titrate hydromorphone hydrochloride extended-release tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving hydromorphone hydrochloride extended-release tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse

  [see Warnings and Precautions ]

  . 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. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

  Plasma levels of hydromorphone hydrochloride extended-release tablets are sustained for 18 to 24 hours. Dosage adjustments of hydromorphone hydrochloride extended-release tablets may be made in increments of 4 to 8 mg every 3 to 4 days as needed to achieve adequate analgesia.

  Patients who experience breakthrough pain may require a dose increase of hydromorphone hydrochloride extended-release tablets, or may need rescue medication with an appropriate dose of an immediate-release analgesic. If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the hydromorphone hydrochloride extended-release tablets dose.

  If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage

  [see Warnings and Precautions ]

  . Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.
  )
• •Do not rapidly reduce or abruptly discontinue hydromorphone hydrochloride extended-release tablets in a physically-dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (
  2.5 Safe Reduction or Discontinuation of Hydromorphone Hydrochloride Extended-Release Tablets

  Do not rapidly reduce or abruptly discontinue hydromorphone hydrochloride extended-release tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

  When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking hydromorphone hydrochloride extended-release tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including hydromorphone hydrochloride extended-release tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.

  There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on hydromorphone hydrochloride extended-release tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.

  It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include 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. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.

  When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic

  [see Warnings and Precautions (

  5.13

  ), Drug Abuse and Dependence ]

  .
  ,
  5.13 Withdrawal

  Do not abruptly discontinue hydromorphone hydrochloride extended-release tablets in a patient physically dependent on opioids. When discontinuing hydromorphone hydrochloride extended-release 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

  [see Dosage and Administration (

  2.5

  ), Drug Abuse and Dependence ]

  .

  Additionally, 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 hydromorphone hydrochloride extended-release tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms

  [see Drug Interactions ]

  .
  )
• •
  Moderate Hepatic Impairment
  : Initiate treatment with 25% of the dose that would be prescribed for patients with normal hepatic function. Monitor closely for respiratory and central nervous system depression. (
  2.6 Dosage Modifications in Patients with Moderate Hepatic Impairment

  Start patients with moderate hepatic impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal hepatic function. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment

  [see Use in Specific Populations ]

  .
  )
• •
  Moderate and Severe Renal Impairment
  : Initiate treatment in patients with moderate renal impairment with 50% and patients with severe renal impairment with 25% of the hydromorphone hydrochloride extended-release dose that would be prescribed for patients with normal renal function. Monitor closely for respiratory and central nervous system depression. (
  2.7 Dosage Modifications in Patients with Renal Impairment

  Start patients with moderate renal impairment on 50% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal renal function. Closely monitor patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. As hydromorphone hydrochloride extended-release tablets are only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment

  [see Use in Specific Populations ]

  .
  )

Extended-release tablets: available in 8 mg, 12 mg, 16 mg or 32 mg dosage strengths.

8 mg tablets: round, biconvex, dark beige tablets imprinted with “P293” over “8” on one side.

12 mg tablets: round, biconvex, white tablets imprinted with “P294” over “12” on one side.

16 mg tablets: round, biconvex, light beige tablets imprinted with “P295” over “16” on one side.

32 mg tablets: round, biconvex, pink tablets imprinted with "P297" over "32" on one side.

• •
  Pregnancy
  : May cause fetal harm. (
  8.1 Pregnancy

  Risk Summary

  Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome

  [see Warnings and Precautions ].

  There are no adequate and well-controlled studies in pregnant women. Based on animal data, advise pregnant women of the potential risk to a fetus.

  In animal reproduction studies, reduced postnatal survival of pups, developmental delays, and altered behavioral responses were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 2.1 times the human daily dose of 32 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 4.8 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 2.3 times the HDD to pregnant mice. No malformations were noted at 2.1 or 17 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 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, and manage accordingly

  [see Warnings and Precautions ]

  .

  Labor or Delivery

  Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent or nalmefene, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone hydrochloride extended-release tablets are not recommended for use in pregnant women during or immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including hydromorphone hydrochloride extended-release 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.

  Data

  Animal Data

  Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day 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 6 to 20 via oral gavage doses of 10, 25, or 50 mg/kg/day (4.3, 8.5, or 17 times the HDD of 32 mg/day based on body surface area, respectively). Maternal toxicity was noted in the highest dose group (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 (4.8 to 65.4 times the HDD of 32 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 (3.5 times the human daily dose of 32 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 (1.1, 2.3, or 4.6 times the human daily dose of 32 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 2.3 times the human dose of 32 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.

  Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to Lactation Day 21 via oral gavage doses of 1.75, 3.5, or 7 mg/kg/day (0.5, 1.1, or 2.1 times the HDD of 32 mg/day based on body surface area, respectively). Reduced pup weights were noted at 1.1 and 2.1 times the human daily dose of 32 mg/day and increased pup deaths, delayed ear opening, reduced auditory startle reflex, and reduced open-field activity were also noted at 2.1 times the HDD. Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in all groups) and decreased maternal care in the high dose group.
  )
• •
  Lactation
  : Not recommended. (
  8.2 Lactation

  Risk Summary

  Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with hydromorphone hydrochloride extended-release tablets. Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving hydromorphone hydrochloride extended-release tablets since hydromorphone is excreted in the milk.

  Clinical Considerations

  Monitor infants exposed to hydromorphone hydrochloride extended-release tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.
  )
• •
  Severe Hepatic Impairment
  : Use not recommended. (
  8.6 Hepatic Impairment

  In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-∞) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be used in patients with normal hepatic function. Regularly evaluate patients with moderate hepatic impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. As further increases in C_maxand AUC_0-∞of hydromorphone in this group are expected, use of alternate analgesics is recommended

  [see Dosage and Administration (

  2.6

  )]

  .
  )
• •
  Severe Renal Impairment
  : Consider an alternate analgesic. (
  8.7 Renal Impairment

  Administration of a single 4 mg dose of immediate-release hydromorphone tablets resulted in two-fold and four-fold increases in plasma levels of hydromorphone (C_maxand AUC_0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life. Start patients with moderate renal impairment on 50% and patients with severe renal impairment on 25% of the hydromorphone hydrochloride extended-release tablets dose that would be prescribed for patients with normal renal function. Regularly evaluate patients with renal impairment for respiratory and central nervous system depression during initiation of therapy with hydromorphone hydrochloride extended-release tablets and during dose titration. As hydromorphone hydrochloride extended-release tablets are only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment

  [see Dosage and Administration (

  2.7

  )]

  .
  )