Hydromorphone Hcl

Hydromorphone Hcl INJECTION is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

Hydromorphone Hcl-HP INJECTION is indicated for use in opioid-tolerant patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate.

Patients considered opioid tolerant are those who are taking for one week or longer,around-the-clock medicine consisting of at least 60 mg oral morphine per day, or at least 25 mcg transdermal fentanyl per hour, or at least 30 mg oral oxycodone per day, or at least 8 g oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid for one week or longer. Patients must remain on around-the-clock opioids while administering Hydromorphone Hcl-HP.

Limitations Of Use

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses , reserve Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

• Have not been tolerated, or are not expected to be tolerated
• Have not provided adequate analgesia, or are not expected to provide adequate analgesia

Hydromorphone Hcl is indicated for the management of pain in opioid-tolerant patients severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

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.

Limitations Of Use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Hydromorphone Hcl for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• Hydromorphone Hcl is not indicated as an as-needed (prn) analgesic.

Important Dosage And Administration Instructions

• Always initiate dosing in opioid-naive patients using Hydromorphone Hcl INJECTION. Never administer Hydromorphone HclHP INJECTION to opioid-naive patients.
• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.
• Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse.
• Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION and adjust the dosage accordingly.
• Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION. No loss of potency has been demonstrated. Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION are physically compatible and chemically stable for at least 24 hours at 25°C, protected from light in most common large-volume parenteral solutions.
• Discard any unused portion in an appropriate manner.

Initial Dosage

Use Of Hydromorphone Hcl INJECTION Or Hydromorphone Hcl-HP INJECTION As The First Opioid Analgesic

Hydromorphone Hcl-HP Injection is for use in opioid tolerant patients only. Do not use Hydromorphone Hcl-HP for patients who are not tolerant to the respiratory depressant or sedating effects of opioids.

Subcutaneous or Intramuscular Administration

The usual starting dose of Hydromorphone Hcl INJECTION is 1 mg to 2 mg every 2 to 3 hours as necessary. Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naive.

Intravenous Administration

The initial starting dose is 0.2 to 1 mg every 2 to 3 hours. Intravenous administration should be given slowly, over at least 2 to 3 minutes, depending on the dose. The initial dose should be reduced in the elderly or debilitated and may be lowered to 0.2 mg.

Conversion From Other Opioids To Hydromorphone Hcl INJECTION Or Hydromorphone Hcl-HP INJECTION:

There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION. It is safer to underestimate a patient’s 24-hour Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION dosage than to overestimate the 24-hour Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION dosage and manage an adverse reaction due to overdose.

If the decision is made to convert to Hydromorphone Hydrochloride Injection from another opioid analgesic using publicly available data, convert the current total daily amount(s) of opioid(s) received to an equivalent total daily dose of Hydromorphone Hcl INJECTION and reduce by one-half due to the possibility of incomplete cross tolerance. Divide the new total amount by the number of doses permitted based on dosing interval (e.g., 8 doses for every-three-hour dosing). Titrate the dose according to the patient's response.

Use Hydromorphone Hcl-HP ONLY for patients who require the higher concentration and lower total volume of Hydromorphone Hcl-HP. Because of its high concentration, the delivery of precise doses of Hydromorphone Hcl-HP INJECTION may be difficult if low doses of hydromorphone are required. Therefore, use Hydromorphone Hcl-HP INJECTION only if the amount of hydromorphone required can be delivered accurately with this formulation.

Base the starting dose for Hydromorphone Hcl-HP INJECTION on the prior dose of Hydromorphone Hcl INJECTION or on the prior dose of an alternate opioid.

Dosage Modifications In Patients With Hepatic Impairment

Start patients with hepatic impairment on one-fourth to one-half the usual Hydromorphone Hcl INJECTION starting dose depending on the extent of impairment.

Dosage Modifications In Patients With Renal Impairment

Start patients with renal impairment on one-fourth to one-half the usual Hydromorphone Hcl INJECTION starting dose depending on the degree of impairment.

Titration And Maintenance Of Therapy

Individually titrate Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration.

If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation Of Hydromorphone Hcl INJECTION Or Hydromorphone Hcl-HP INJECTION

When a patient who has been taking Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION regularly and may be physically dependent no longer requires therapy with Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION in a physically-dependent patient.

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 Hcl should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

Due to the risk of respiratory depression, Hydromorphone Hcl is only indicated for use in patients who are already opioid-tolerant. Discontinue or taper all other extended-release opioids when beginning Hydromorphone Hcl therapy. As Hydromorphone Hcl is only for use in opioid-tolerant patients, do not begin any patient on Hydromorphone Hcl 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 consistent with individual patient treatment goals.
• Initiate the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse.
• Monitor patients closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and following dosage increases with Hydromorphone Hcl and adjust the dosage accordingly.

Instruct patients to swallow Hydromorphone Hcl tablets whole. Crushing, chewing, or dissolving Hydromorphone Hcl tablets will result in uncontrolled delivery of hydromorphone and can lead to overdose or death.

Initial Dosage

Conversion From Other Oral Hydromorphone Formulations To Hydromorphone Hcl

Patients receiving oral immediate-release hydromorphone may be converted to Hydromorphone Hcl by administering a starting dose equivalent to the patient’s total daily oral hydromorphone dose, taken once daily.

Conversion From Other Oral Opioids To Hydromorphone Hcl

Discontinue all other around-the-clock opioid drugs when Hydromorphone Hcl therapy is initiated.

There is substantial inter-patient variability in the relative potency of different opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Hydromorphone Hcl. It is safer to underestimate a patient’s 24-hour oral hydromorphone dosage and provide rescue medication (e.g., immediate-release opioid) than to overestimate the 24-hour oral hydromorphone dosage and manage an adverse reaction due to overdose.

In an Hydromorphone Hcl clinical trial with an open-label titration period, patients were converted from their prior opioid to Hydromorphone Hcl using the Table 1 as a guide for the initial Hydromorphone Hcl dose. The recommended starting dose of Hydromorphone Hcl is 50% of the calculated estimate of daily hydromorphone requirement. Calculate the estimated daily hydromorphone requirement using Table 1.

Consider the following when using the information in Table 1:

• This is not a table of equianalgesic doses.
• The conversion factors in this table are only for the conversion from one of the listed oral opioid analgesics to Hydromorphone Hcl.
• The table cannot be used to convert from Hydromorphone Hcl to another opioid. Doing so will result in an overestimation of the dose of the new opioid and may result in fatal overdose.

Table 1. Conversion Factors to Hydromorphone Hcl

To calculate the estimated Hydromorphone Hcl dose using Table 1:

• For patients on a single opioid, sum the current total daily dose of the opioid and then multiply the total daily dose by the conversion factor to calculate the approximate oral hydromorphone daily dose.
• For patients on a regimen of more than one opioid, calculate the approximate oral hydromorphone dose for each opioid and sum the totals to obtain the approximate total hydromorphone daily dose.
• For patients on a regimen of fixed-ratio opioid/non-opioid analgesic products, use only the opioid component of these products in the conversion.

Always round the dose down, if necessary, to the appropriate Hydromorphone Hcl strength(s) available.

Example conversion from a single opioid to Hydromorphone Hcl:

Step 1: Sum the total daily dose of the opioid

• 30 mg of oxycodone 2 times daily = 60 mg total daily dose of oxycodone

Step 2: Calculate the approximate equivalent dose of oral hydromorphone based on the total daily dose of the current opioid using Table 1

• 60 mg total daily dose of oxycodone x Conversion Factor of 0.4 = 24 mg of oral hydromorphone daily

Step 3: Calculate the approximate starting dose of Hydromorphone Hcl to be given every 24 hours, which is 50% of the calculated oral hydromorphone dose. Round down, if necessary, to the appropriate Hydromorphone Hcl tablet strengths available.

• 50% of 24 mg results in an initial dose of 12 mg of Hydromorphone Hcl once daily
• Adjust individually for each patient

Close observation and frequent titration are warranted until pain management is stable on the new opioid.

Monitor patients for signs and symptoms of opioid withdrawal or for signs of over-sedation/toxicity after converting patients to Hydromorphone Hcl.

Conversion From Transdermal Fentanyl To Hydromorphone Hcl

Eighteen hours following the removal of the transdermal fentanyl patch, Hydromorphone Hcl treatment can be initiated. To calculate the 24-hour Hydromorphone Hcl dose, use a conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Hydromorphone Hcl. Then reduce the Hydromorphone Hcl dose by 50%.

For example:

Step 1: Identify the dose of transdermal fentanyl.

• 75 mg of transdermal fentanyl

Step 2: Use the conversion factor of 25 mcg/hr fentanyl transdermal patch to 12 mg of Hydromorphone Hcl.

• 75 mg of transdermal fentanyl : 36 mg total daily dose of Hydromorphone Hcl

Step 3: Calculate the approximate starting dose of Hydromorphone Hcl to be given every 24 hours, which is 50% of the converted dose. Round down, if necessary, to the appropriate Hydromorphone Hcl tablet strengths available.

• 50% of 36 mg results in an initial dose of 18 mg, which would be rounded down to 16 mg of Hydromorphone Hcl once daily
• Adjust individually for each patient

Conversion From Methadone To Hydromorphone Hcl

Close monitoring is of particular importance when converting from methadone to other opioid agonists.

The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Titration And Maintenance Of Therapy

Individually titrate Hydromorphone Hcl to a dose that provides adequate analgesia and minimizes adverse reactions.

Continually reevaluate patients receiving Hydromorphone Hcl to assess the maintenance of pain control and the relative incidence of adverse reactions, as well as monitoring for the development of addiction, abuse, or misuse. 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 chronic therapy, periodically reassess the continued need for opioid analgesics.

Plasma levels of Hydromorphone Hcl are sustained for 18 to 24 hours. Dosage adjustments of Hydromorphone Hcl 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 Hcl, 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 Hcl dose.

If unacceptable opioid-related adverse reactions are observed, the subsequent doses may be reduced. Adjust the dose to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Discontinuation Of Hydromorphone Hcl

When a patient no longer requires therapy with Hydromorphone Hcl, taper doses gradually, by 25% to 50% every 2 to 3 days while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue Hydromorphone Hcl.

To dispose of unused Hydromorphone Hcl flush all remaining tablets down the toilet or remit to authorities at a certified drug take-back program.

Dosage Modifications In Patients With Moderate Hepatic Impairment

Start patients with moderate hepatic impairment on 25% of the Hydromorphone Hcl 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 Hcl and during dose titration. Use of alternate analgesics is recommended for patients with severe hepatic impairment.

Dosage Modifications In Patients With Renal Impairment

Start patients with moderate renal impairment on 50% of the Hydromorphone Hcl 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 Hcl and during dose titration. As Hydromorphone Hcl is 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.

Both Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION 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)

Hydromorphone Hcl-HP INJECTION is contraindicated in patients who are not opioid tolerant.

Hydromorphone Hcl is contraindicated in:

• Opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.
• 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.
• Patients who have had surgical procedures and/or underlying disease resulting in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction.
• Patients with hypersensitivity (e.g., anaphylaxis) to hydromorphone

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Medication Errors

Hydromorphone Hcl-HP INJECTION is a 10 mg/mL concentrated solution of hydromorphone, and is intended for use in opioid-tolerant patients only. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer.

Do not confuse Hydromorphone Hcl-HP INJECTION with standard parenteral formulations of Hydromorphone Hcl INJECTION (0.5 mg/0.5 mL, 1 mg/mL, 2 mg/mL, 4 mg/mL) or other opioids, as overdose and death could result.

Addiction, Abuse, And Misuse

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION contain hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION 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 Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, and monitor all patients receiving Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. 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 Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION.

To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hcl INJECTION or Hydromorphone HclHP INJECTION are essential. Overestimating the Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Hydromorphone Hcl-HP INJECTION is for use in opioid-tolerant patients only. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

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 Hcl or Hydromorphone Hcl-HP Injection with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

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 Hydromorphone Hcl or Hydromorphone Hcl-HP Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

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

The use of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients With Chronic Pulmonary Disease

Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION.

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 Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION and when Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION are given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

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.

Severe Hypotension

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION. In patients with circulatory shock, Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION in patients with circulatory shock.

Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION in patients with impaired consciousness or coma.

Risks Of Use In Patients With Gastrointestinal Conditions

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The hydromorphone in Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk Of Seizures In Patients With Seizure Disorders

The hydromorphone in Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.

When discontinuing Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, in a physically-dependent patient, gradually taper the dosage. Do not abruptly discontinue Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION in these patients.

Risks Of Driving And Operating Machinery

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION and know how they will react to the medication.

Sulfites

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Increased Risk Of Hypotension And Respiratory Depression With Rapid Intravenous Administration

Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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

Mutagenesis

Hydromorphone was positive in the mouse lymphoma assay in the presence of metabolic activation, but was negative in the mouse lymphoma assay in the absence of metabolic activation. Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.

Impairment Of Fertility

Reduced implantation sites and viable fetuses were noted at 2.1 times the human daily dose of 32 mg/day in a study in which female rats were treated orally with 1.75, 3.5, or 7 mg/kg/day hydromorphone hydrochloride (0.5, 1.1, or 2.1 times a human daily dose of 24 mg/day (HDD) based on body surface area) beginning 14 days prior to mating through Gestation Day 7 and male rats were treated with the same hydromorphone hydrochloride doses beginning 28 days prior to and throughout mating.

Use In Specific Populations

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. There are no available data with Hydromorphone Hcl injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, reduced postnatal survival of pups, and decreased were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 0.8 times the human daily dose of 24 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No malformations were noted at 4 or 40.5 times the HDD in pregnant rats or rabbits, respectively. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data

Animal Data

Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1, 5, or 10 mg/kg/day (0.4, 2, or 4 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in the two highest dose groups). There was no evidence of malformations or embryotoxicity reported.

Pregnant rabbits were treated with hydromorphone hydrochloride from Gestation Day 7 to 19 via oral gavage doses of 10, 25, or 50 mg/kg/day (8.1, 20.3, or 40.5 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in the two highest dose groups (reduced food consumption and body weights). There was no evidence of malformations or embryotoxicity reported.

In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the human daily dose of 24 mg/day).

In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.

Increased pup mortality and decreased pup body weights were noted at 0.8 and 2 times the human daily dose of 24 mg in a study in which pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 7 to Lactation Day 20 via oral gavage doses of 0, 0.5, 2, or 5 mg/kg/day (0.2, 0.8, or 2 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity (decreased food consumption and body weight gain) was also noted at the two highest doses tested.

Lactation

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 Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION and any potential adverse effects on the breastfed infant from Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphone is stopped, or when breast-feeding is stopped.

Females And Males Of Reproductive Potential

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.

Pediatric Use

The safety and effectiveness of Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION in pediatric patients has not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION 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.

Hepatic Impairment

The pharmacokinetics of hydromorphone are affected by hepatic impairment. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at one-fourth to one-half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose.

Renal Impairment

The pharmacokinetics of hydromorphone are affected by renal impairment. Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Addiction, Abuse, And Misuse

Hydromorphone Hcl contains hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hcl exposes users to the risks of addiction, abuse, and misuse. As modified- release products such as Hydromorphone Hcl deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hcl and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hcl, and monitor all patients receiving Hydromorphone Hcl 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 Hcl for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as Hydromorphone Hcl, but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hcl along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of Hydromorphone Hcl by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death.

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Hydromorphone Hcl. 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.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modifiedrelease 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. 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 Hcl, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with Hydromorphone Hcl and following dosage increases.

To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hcl are essential. Overestimating the Hydromorphone Hcl 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 Hcl, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Hydromorphone Hcl 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.

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 Hcl 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 Hydromorphone Hcl is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

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

The use of Hydromorphone Hcl 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 Hcl 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 Hcl.

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 Hydromorphone Hcl and when Hydromorphone Hcl is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.

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.

Severe Hypotension

Hydromorphone Hcl 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). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydromorphone Hcl. In patients with circulatory shock, Hydromorphone Hcl may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hcl in patients with circulatory shock.

Risks Of Use In Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, Or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Hydromorphone Hcl 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 Hydromorphone Hcl.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Hydromorphone Hcl in patients with impaired consciousness or coma.

Risks Of Use In Patients With Gastrointestinal Conditions

Hydromorphone Hcl is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Avoid the use of Hydromorphone Hcl in patients with other GI obstruction.

Because the Hydromorphone Hcl tablet is nondeformable and does not appreciably change in shape in the GI tract, Hydromorphone Hcl is 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 Hcl tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

The hydromorphone in Hydromorphone Hcl may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk Of Seizures In Patients With Seizure Disorders

The hydromorphone in Hydromorphone Hcl 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 Hydromorphone Hcl therapy.

Withdrawal

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydromorphone Hcl. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing Hydromorphone Hcl, gradually taper the dose. Do not abruptly discontinue Hydromorphone Hcl.

Sulfites

Hydromorphone Hcl contains 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.

Risks Of Driving And Operating Machinery

Hydromorphone Hcl 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 Hcl and know how they will react to the medication.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Addiction, Abuse, And Misuse

Inform patients that the use of Hydromorphone Hcl, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share Hydromorphone Hcl with others and to take steps to protect Hydromorphone Hcl from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydromorphone Hcl or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death. Instruct patients to take steps to store Hydromorphone Hcl securely and to dispose of unused Hydromorphone Hcl by flushing the tablets down the toilet.

Interactions With Benzodiazepines And Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Hydromorphone Hcl is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider.

Serotonin Syndrome

Inform patients that Hydromorphone Hcl could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications.

MAOI Interaction

Inform patients to avoid taking Hydromorphone Hcl while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Hydromorphone Hcl.

Adrenal Insufficiency

Inform patients that Hydromorphone Hcl could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.

Important Administration Instructions

Instruct patients how to properly take Hydromorphone Hcl, including the following:

• Hydromorphone Hcl is designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved Hydromorphone Hcl tablets can result in a fatal overdose.
• Using Hydromorphone Hcl exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
• Do not discontinue Hydromorphone Hcl without first discussing the need for a tapering regimen with the prescriber.

Gastrointestinal Blockage

Advise patients that people with certain stomach or intestinal problems such as narrowing of the intestines or previous surgery may be at higher risk of developing a blockage. Symptoms include abdominal distension, abdominal pain, severe constipation, or vomiting. Instruct patients to contact their healthcare provider immediately if they develop these symptoms.

Hypotension

Inform patients that Hydromorphone Hcl may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Hydromorphone Hcl. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Hydromorphone Hcl during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Hydromorphone Hcl can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise patients that breastfeeding is not recommended during treatment with Hydromorphone Hcl

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Driving Or Operating Heavy Machinery

Inform patients that Hydromorphone Hcl may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Disposal Of Unused Hydromorphone Hcl

Advise patients to flush the unused tablets down the toilet when Hydromorphone Hcl is no longer needed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of hydromorphone hydrochloride were completed in both Han-Wistar rats and Crl:CD1^®(ICR) mice. Hydromorphone HCl was administered to Han-Wistar rats (2, 5, and 15 mg/kg/day for males, and 8, 25 and 75 mg/kg/day for females) for 2 years by oral gavage. In female rats, incidences of hibernoma (tumor of brown fat) were increased at 10.5 times the maximum recommended daily exposure based on AUC at the mid dose (2 tumor, 25 mg/kg/day) and 53.7 times the maximum recommended human daily exposure based on AUC at the maximum dose (4 tumors, 75 mg/kg/day). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in male rats. The systemic drug exposure (AUC, ng•h/mL) at the 15 mg/kg/day in male rats was 7.6 times greater than the human exposure at a single dose of 32 mg/day of Hydromorphone Hcl. There was no evidence of carcinogenic potential in Crl:CD1^®(ICR) mice administered hydromorphone HCl at doses up to 15 mg/kg/day for 2 years by oral gavage. The systemic drug exposure (AUC, ng•h/mL) at the 15 mg/kg/day in mice was 1.1 (in males) and 1.2 (in females) times greater than the human exposure at a single dose of 32 mg/day of Hydromorphone Hcl.

Mutagenesis

Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.

Impairment Of Fertility

Reduced implantation sites and viable fetuses were noted at 2.1 times the human daily dose of 32 mg/day in a study in which female rats were treated orally with 1.75, 3.5, or 7 mg/kg/day hydromorphone hydrochloride (0.7, 1.4, or 2.8 times a human daily dose of 24 mg/day (HDD) based on body surface area) beginning 14 days prior to mating through Gestation Day 7 and male rats were treated with the same hydromorphone hydrochloride doses beginning 28 days prior to and throughout mating.

Use In Specific Populations

Pregnancy

Risk Summary

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. 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. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

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

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone Hcl is 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 Hcl 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

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 Hcl. 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 Hcl since hydromorphone is excreted in the milk.

Clinical Considerations

Monitor infants exposed to Hydromorphone Hcl 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.

Females And Males Of Reproductive Potential

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.

Pediatric Use

The safety and effectiveness of Hydromorphone Hcl in patients 17 years of age and younger have not been established.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were coadministered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hcl 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.

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 Hcl dose that would be used in 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 Hcl and during dose titration. The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. As further increases in Cmax and AUC0-∞ of hydromorphone in this group are expected, use of alternate analgesics is recommended.

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 (Cmax and AUC0-48h) 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 Hcl 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 Hcl and during dose titration. As Hydromorphone Hcl is 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.

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 and Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal

The following adverse reactions associated with the use of hydromorphone were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.

Serious adverse reactions associated with Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest.

The most common adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain.

Less Frequently Observed Adverse Reactions

Cardiac disorders: tachycardia, bradycardia, palpitations

Eye disorders: vision blurred, diplopia, miosis, visual impairment

Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain

General disorders and administration site conditions: weakness, feeling abnormal, chills, injection site urticaria, fatigue, injection site reactions, peripheral edema

Hepatobiliary disorders: biliary colic

Immune system disorders: anaphylactic reactions, hypersensitivity reactions

Investigations: hepatic enzymes increased

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle rigidity

Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration, involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence

Psychiatric disorders: agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams

Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling

Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis

Vascular disorders: flushing, hypotension, hypertension

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 Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Addiction, Abuse, and Misuse
• Life Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Interactions with Benzodiazepine or Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Hydromorphone Hcl was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to Hydromorphone Hcl for greater than 6 months and 141 exposed for greater than one year.

The most common adverse reactions leading to study discontinuation were nausea, vomiting, constipation, somnolence, and dizziness. The most common treatment-related serious adverse reactions from controlled and uncontrolled chronic pain studies were drug withdrawal syndrome, overdose, confusional state, and constipation.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients.

The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 2.

Table 2. Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 3.

Table 3.
Number (%) of Patients with Adverse Reactions Reported in ≥ 2% of Patients with Chronic Pain Receiving Hydromorphone Hcl in 14 Clinical Studies by Preferred Term

The following Adverse Reactions occurred in patients with an overall frequency of < 2% and are listed in descending order within each System Organ Class:

Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles

Ear and labyrinth disorders: vertigo, tinnitus

Endocrine disorders: hypogonadism

Eye disorders: vision blurred, diplopia, dry eye, miosis

Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation

General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling of body temperature change, feeling jittery, hangover, gait disturbance, feeling drunk, body temperature decreased

Infections and infestations: gastroenteritis, diverticulitis

Injury, poisoning and procedural complications: contusion, overdose

Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased

Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia

Musculoskeletal and connective tissue disorders: myalgia

Nervous system disorders: tremor, sedation, hypoesthesia, paresthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, crying, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity

Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, suicide ideation, libido decreased, aggression

Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder

Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: rhinorrhea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression

Skin and subcutaneous tissue disorders: erythema

Vascular disorders: flushing, hypertension, hypotension

Postmarketing Experience

The following adverse reactions have been identified during post approval use of hydromorphone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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: Anaphylactic reaction has been reported with ingredients contained in Hydromorphone Hcl.

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

Clinical Presentation

Acute overdose with Hydromorphone Hcl INJECTION or Hydromorphone Hcl-HP INJECTION can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations.

Treatment Of Overdose

In case of overdose, priorities are the reestablishment of a patent airway and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.

The opioid antagonists, naloxone or nalmefene are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydromorphone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose.

Because the duration of opioid reversal is expected to be less than the duration of hydromorphone in Hydromorphone Hcl INJECTION and Hydromorphone Hcl-HP INJECTION, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Clinical Presentation

Acute overdosage with Hydromorphone Hcl can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment Of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone and nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydromorphone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose.

Because the duration of reversal is expected to be less than the duration of action of hydromorphone in Hydromorphone Hcl, carefully monitor the patient until spontaneous respiration is reliably reestablished. Hydromorphone Hcl will continue to release hydromorphone and add to the hydromorphone load for up to 24 to 48 hours or longer following ingestion, necessitating prolonged monitoring. If the response to opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experiences will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

Effects On The Central Nervous System

Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects On The Gastrointestinal Tract And Other Smooth Muscle

Hydromorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects On The Cardiovascular System

Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope, manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating and/or orthostatic hypotension.

Effects On The Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Effects On The Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration-Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydromorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

Concentration-Adverse Reaction

Relationships There is a relationship between increasing hydromorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when Hydromorphone Hcl is used in conjunction with alcohol, other opioids, legal or illicit drugs that cause central nervous system depression.

Effects On The Central Nervous System

Hydromorphone produces dose-related respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and to electrical stimulation.

Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis, rather than miosis, may be seen due to severe hypoxia in overdose situations.

Effects On The Gastrointestinal Tract And Other Smooth Muscle

Hydromorphone causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects On The Cardiovascular System

Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by hydromorphone and can contribute to opioid-induced hypotension. Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, sweating and/or orthostatic hypotension.

Effects On The Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

Effects On The Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of hydromorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance.

Concentration–Adverse Reaction Relationships

There is a relationship between increasing hydromorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

Distribution

At therapeutic plasma levels, hydromorphone is approximately 8-19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%CV)] is 302.9 (32%) liters.

Elimination

The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours.

Metabolism

Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Excretion

Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites.

Absorption

Hydromorphone Hcl is an extended-release formulation of hydromorphone that produces a gradual increase in hydromorphone concentrations. Following a single-dose administration of Hydromorphone Hcl, plasma concentrations gradually increase over 6 to 8 hours, and thereafter concentrations are sustained for approximately 18 to 24 hours post-dose. The median Tmax values ranged from 12 to 16 hours. The mean half-life was approximately 11 hours, ranging from 8 to 15 hours in most individual subjects. Linear pharmacokinetics has been demonstrated for Hydromorphone Hcl over the dose range 8 to 64 mg, with a doseproportional increase in Cmax and overall exposure (AUC0-∞) (see Table 4). Steady-state plasma concentrations are approximately twice those observed following the first dose, and steady state is reached after 3 to 4 days of once-daily dosing of Hydromorphone Hcl. At steady state, Hydromorphone Hcl given once daily maintained hydromorphone plasma concentrations within the same concentration range as the immediate-release tablet given 4 times daily at the same total daily dose and diminished the fluctuations between peak and trough concentrations seen with the immediate-release tablet (see Figure 1). The bioavailability of Hydromorphone Hcl once daily and immediate-release hydromorphone four times daily in adults is comparable, as presented in Table 4.

Figure 1. Mean Steady-State Plasma Concentration Profile

Table 5. Mean (±SD) Hydromorphone Hcl Pharmacokinetic Parameters

Food Effect

The pharmacokinetics of Hydromorphone Hcl are not affected by food as indicated by bioequivalence when administered under fed and fasting conditions. Therefore, Hydromorphone Hcl may be administered without regard to meals. When a 16 mg dose of Hydromorphone Hcl was administered to healthy volunteers immediately following a high-fat meal, the median time to Cmax (Tmax) was minimally affected by the high-fat meal occurring at 16 hours compared to 18 hours while fasting.

Distribution

Following intravenous administration of hydromorphone to healthy volunteers, the mean volume of distribution was 2.9 (±1.3) L/kg, suggesting extensive tissue distribution. The mean extent of binding of hydromorphone to human plasma proteins was determined to be 27% in an in vitro study.

Elimination

Metabolism

After oral administration of an immediate-release formulation, hydromorphone undergoes extensive firstpass metabolism and is metabolized primarily in the liver by glucuronidation to hydromorphone-3- glucuronide, which follows a similar time course to hydromorphone in plasma. Exposure to the glucuronide metabolite is 35 to 40 times higher than exposure to the parent drug. In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

Excretion

Approximately 75% of the administered dose is excreted in urine. Most of the administered hydromorphone dose is excreted as metabolites. Approximately 7% and 1% of the dose are excreted as unchanged hydromorphone in urine and feces, respectively.