These Highlights Do Not Include All The Information Needed To Use Hydromorphone Hydrochloride Injection Safely And Effectively. See Full Prescribing Information For Hydromorphone Hydrochloride Injection.

Addiction, Abuse, and Misuse

Because use of Hydromorphone Hydrochloride Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Safety and Handling Instructions

Access to drugs with a potential for abuse such as Hydromorphone Hydrochloride Injection presents an occupational hazard for addiction in the health care industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect health care workers. Implementation of more effective accounting procedures and measures to restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-administration by health care providers.

Hydromorphone Hydrochloride Injection contains hydromorphone, a substance with high potential for misuse and abuse, which can lead to the development of ‎substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than ‎‎prescribed by a healthcare provider or for ‎whom it was not prescribed.‎

Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug, use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Hydromorphone Hydrochloride Injection increases ‎risk of overdose, which may lead to ‎central nervous system and ‎respiratory depression, hypotension, seizures, and death. The risk is ‎increased with ‎concurrent abuse of Hydromorphone Hydrochloride ‎Injection with alcohol and/or other CNS ‎depressants.‎ Abuse of and addiction to opioids in some individuals may not be ‎accompanied by concurrent ‎tolerance and symptoms of physical ‎dependence. In addition, abuse of opioids can occur in the absence of ‎‎addiction.‎

All patients treated with opioids require careful and frequent reevaluation ‎for signs of misuse, abuse, and ‎addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate ‎medical use. ‎Patients at high risk of Hydromorphone Hydrochloride Injection abuse ‎include those with a ‎history of prolonged use of any opioid, including products containing ‎hydromorphone, those with a history of drug or alcohol abuse, ‎or those ‎who use Hydromorphone Hydrochloride Injection in combination with ‎other abused drugs.‎

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Hydromorphone Hydrochloride Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Hydromorphone Hydrochloride Injection is available as an aqueous sterile solution, for use in intravenous, intramuscular and subcutaneous administration, and contains hydromorphone as active pharmaceutical ingredient in the form hydrochloride salt. Hydromorphone hydrochloride is an opioid agonist.

The chemical name of hydromorphone hydrochloride is 4,5α- epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 321.8 and it has the following chemical structure.

Hydromorphone hydrochloride is a white or almost white crystalline powder that is freely soluble in water, very slightly soluble in ethanol (96%), and practically insoluble in methylene chloride.

Each mL of Hydromorphone Hydrochloride Injection sterile solution contains 0.5 mg, 1 mg or 2 mg of Hydromorphone Hydrochloride USP, equivalent to 0.44 mg, 0.89 mg or 1.77 mg of hydromorphone free base, respectively, 0.24 mg of Lactic Acid USP, 5.40 mg of Sodium Chloride as isotonicity agent, 8.93 mg of Sodium Lactate USP as buffering agent, and Lactic Acid USP and Sodium Hydroxide NF as pH adjusters, in Water for Injection. Hydromorphone Hydrochloride Injection pH range is 3.5 to 5.5.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to ‎a drug after repeated administration (i.e., a ‎higher ‎dose of a drug is ‎required to produce the same effect that was once obtained at a lower ‎dose).‎

Physical dependence is a state that develops as a result of a physiological ‎adaptation in response to repeated drug use, ‎manifested ‎by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Hydromorphone Hydrochloride Injection should not be rapidly reduced or abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6)]. If Hydromorphone Hydrochloride Injection is rapidly reduced or abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically ‎characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically-dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydromorphone Hydrochloride Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Hydromorphone Hydrochloride Injection, in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in these patients [see Drug Abuse and Dependence (9.3)].

The safety and effectiveness of Hydromorphone Hydrochloride Injection in pediatric patients has not been established.

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

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydromorphone Hydrochloride Injection is contraindicated in patients with:

• •
  Significant respiratory depression [see Warnings and Precautions (5.2)]
• •
  Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)]
• •
  Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)]
• •
  Hypersensitivity to hydromorphone (e.g., anaphylaxis) [see Adverse Reactions (6)]

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

• •
  Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• •
  Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• •
  Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
• •
  Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• •
  Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.5)]
• •
  Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• •
  Severe Hypotension [see Warnings and Precautions (5.8)]
• •
  Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
• •
  Seizures [see Warnings and Precautions (5.11)]
• •
  Withdrawal [see Warnings and Precautions (5.12)]

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.

The most common adverse effects are light-headedness, 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.

Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Injection.

The pharmacokinetics of hydromorphone are affected by renal impairment. In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life. Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Clinical Pharmacology (12.3)].

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to ‎‎‎administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it ‎‎is ‎discolored in any other way, or if it contains a precipitate.‎

NexJect™ Single-dose Prefilled Syringe

Instructions for use – NexJect Prefilled Syringe

NOTE: To prevent needlestick injuries, do not recap, purposely bend, or break by hand used ‎needles. Do not recap, purposely bend, or break by ‎hand blunt Cannulas.

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1382-3.0

Revised: 12/2023

When a patient who has been taking Hydromorphone Hydrochloride Injection regularly and may be physically dependent no longer requires therapy with Hydromorphone Hydrochloride 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 rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in patients who may be physically dependent on opioids [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Hydromorphone Hydrochloride Injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydromorphone Hydrochloride Injection. In patients with circulatory shock, Hydromorphone Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hydrochloride Injection in patients with circulatory shock.

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 C_max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Clinical Pharmacology (12.3)].

Hydromorphone Hydrochloride Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Hydromorphone is a full opioid agonist and is relatively selective for the mµ-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of hydromorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance.

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.

• •
  Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced ‎Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an ‎increase in pain, or an increase in ‎sensitivity to pain. If OIH is suspected, carefully consider appropriately ‎‎decreasing the dose of the current opioid analgesic, or ‎opioid rotation. (5.5)‎
• •
  Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.6)
• •
  Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.7)
• •
  Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Hydromorphone Hydrochloride Injection in patients with circulatory shock. (5.8)
• •
  Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Hydromorphone Hydrochloride Injection in patients with impaired consciousness or coma. (5.9)

• •
  Hydromorphone Hydrochloride Injection should be ‎prescribed only by healthcare professionals who are ‎knowledgeable about the use of opioids ‎and how to ‎mitigate the associated risks. (2.1)‎
• •
  Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of Hydromorphone ‎Hydrochloride Injection for ‎patients in whom lower doses are insufficiently ‎effective and in whom the expected benefits of using a higher dose opioid ‎clearly outweigh ‎the substantial risks. (2.1, 5)
• •
  Many acute pain conditions (e.g., the pain that occurs with ‎a number of surgical procedures or acute ‎musculoskeletal injuries) require no more ‎than a few ‎days of an opioid analgesic. Clinical guidelines on ‎opioid prescribing for some acute pain conditions are ‎available. (2.1)
• •
  Initiate the dosing regimen for each patient individually, ‎taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1)
• •
  Respiratory depression can occur at any time during opioid ‎therapy, especially when initiating and following dosage ‎increases with ‎Hydromorphone Hydrochloride Injection. ‎Consider this risk when selecting an initial dose and when ‎making dose adjustments. (2.1, 5.2)‎
• •
  Intramuscular and Subcutaneous Use: The usual starting dose is 1 mg to 2 mg every 2 to 3 hours as necessary. (2.2)
• •
  Intravenous Use: The usual starting dose is 0.2 mg to 1 mg every 2 to 3 hours. The injection should be given slowly, over at least 2 to 3 minutes. (2.2)
• •
  Hepatic Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of hepatic impairment. (2.3)
• •
  Renal Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. (2.4)
• •
  Periodically reassess patients receiving Hydromorphone Hydrochloride Injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.5)
• •
  Do not rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient. (2.6, 5.12)

Hydromorphone Hydrochloride Injection, USP is available as:

The drug product is a clear, colorless to nearly colorless aqueous sterile solution. Each 1 mL of sterile solution contains 0.5 mg, 1 mg or 2 mg of hydromorphone hydrochloride.

• •
  Pregnancy: May cause fetal harm. (8.1)
• •
  Geriatric Patients: Use caution during dose selection, starting at the low ‎end of the dosing range while carefully monitoring for side effects. ‎‎(8.5)

Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hydrochloride Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6)].

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hydrochloride Injection, and monitor all patients receiving Hydromorphone Hydrochloride 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 Hydrochloride Injection but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Injection along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Consider these risks when prescribing or dispensing Hydromorphone Hydrochloride 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.

Use of Hydromorphone Hydrochloride Injection for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection. Individually titrate Hydromorphone Hydrochloride Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydromorphone Hydrochloride Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.12)]. 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 Hydrochloride Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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 overdose reversal agent (e.g., naloxone, nalmefene), depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydromorphone Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential [see Dosage and Administration (2.1)]. Overestimating the Hydromorphone Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.1)].

Hydromorphone Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The hydromorphone in Hydromorphone Hydrochloride 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.

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

Hydromorphone Hydrochloride 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 Hydrochloride Injection and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an increase in pain, or an ‎increase in sensitivity to pain. ‎This condition differs from tolerance, which is the need for increasing doses of ‎opioids to ‎maintain a defined effect [Drug Abuse and Dependence (9.3)]. Symptoms of OIH ‎include (but may not be limited to) increased levels ‎of pain upon opioid dosage ‎increase, decreased levels of pain upon opioid dosage decrease, or pain from ‎ordinarily non‑‎painful stimuli (allodynia). These symptoms may suggest OIH only ‎if there is no evidence of underlying disease ‎progression, opioid tolerance, ‎opioid withdrawal, or addictive behavior.‎

Cases of OIH have been reported, both with short-term and longer-term use of ‎opioid analgesics. Though the ‎mechanism of OIH is not fully understood, ‎multiple biochemical pathways have been implicated. Medical literature ‎suggests ‎a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a ‎patient is suspected to be experiencing OIH, ‎carefully consider appropriately ‎decreasing the dose of the current opioid analgesic or opioid rotation (safely ‎switching ‎the patient to a different opioid moiety) [see Dosage and ‎Administration (2.6), Warnings and Precautions (5.12)].‎

HYDROmorphone HCl

Injection, USP

PAA140442

CII

1 mg/mL

HYDROmorphone HCl

Injection, USP

PAA140441

CII

2 mg/mL

• •
  Hydromorphone Hydrochloride Injection should be prescribed only by healthcare ‎professionals who are knowledgeable about the use of opioids and how to ‎mitigate the associated risks.
• •
  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because ‎the risk of overdose increases as opioid doses increase, reserve titration to ‎higher doses of Hydromorphone Hydrochloride Injection for patients in whom ‎lower doses are insufficiently effective and in whom the expected benefits of ‎using a higher dose opioid clearly outweigh the substantial risks.‎
• •
  Many acute pain conditions (e.g., the pain that occurs with a number of surgical ‎procedures or acute musculoskeletal injuries) require no more than a few days ‎of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute ‎pain conditions are available.
• •
  There is variability in the opioid analgesic dose and duration needed to ‎adequately manage pain due both to the cause of pain and to individual patient ‎factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• •
  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydromorphone Hydrochloride Injection. Consider this risk when selecting an initial dose and ‎when making dose adjustments [see Warnings and Precautions (5)].
• •
  Inspect Hydromorphone Hydrochloride Injection for particulate matter and discoloration prior to administration. A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is 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.

HYDROmorphone HCl

Injection, USP

PAA152907

CII

0.5 mg/0.5 mL

HYDROmorphone HCl

Injection, USP

PAA208366

CII

0.25 mg/0.5 mL

TWIST & PULL

Tamper Seal

NDC 0409-1283-17

CII

HYDROmorphone HCl

Injection, USP

1 mg/mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

1 mL Single-dose syringe

PAA140444

LOT #####AA

EXP DMMMYYYY

TWIST & PULL

Tamper Seal

NDC 0409-1312-16

CII

HYDROmorphone HCl

Injection, USP

2 mg/mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

1 mL Single-dose syringe

PAA140445

LOT #####AA

EXP DMMMYYYY

Start patients with renal impairment on one-fourth to one-half the usual starting dose of Hydromorphone Hydrochloride Injection depending on the degree of impairment [see Clinical Pharmacology (12.3)].

NDC 0409-1283-37

HYDROmorphone HCl

Injection, USP

CII

1 mg / mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 1 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each mL contains 1 mg hydromorphone hydrochloride, 0.24 mg of lactic acid,

5.40 mg sodium chloride as isotonicity agent, 8.93 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211792

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

NDC 0409-1312-36

HYDROmorphone HCl

Injection, USP

CII

2 mg / mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 1 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each mL contains 2 mg hydromorphone hydrochloride, 0.24 mg of lactic acid,

5.40 mg sodium chloride as isotonicity agent, 8.93 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211791

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

Start patients with hepatic impairment on one-fourth to one-half the usual dose of Hydromorphone Hydrochloride Injection depending on the extent of impairment [see Clinical Pharmacology (12.3)].

TWIST & PULL

Tamper Seal

NDC 0409-4264-11

CII

HYDROmorphone HCl

Injection, USP

0.5 mg/0.5 mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

0.5 mL Single-dose syringe

PAA152909

LOT #####AA

EXP DMMMYYYY

TWIST & PULL

Tamper Seal

NDC 0409-1805-10

CII

HYDROmorphone HCl

Injection, USP

0.25 mg/0.5 mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

0.5 mL Single-dose syringe

PAA208364

LOT AA####

EXP YYYY / MM

NDC 0409-4264-01

HYDROmorphone HCl

Injection, USP

CII

0.5 mg / 0.5 mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 0.5 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each 0.5 mL contains 0.5 mg hydromorphone hydrochloride, 0.12 mg of lactic acid,

2.70 mg sodium chloride as isotonicity agent, 4.47 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211659

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

NDC 0409-1805-01

HYDROmorphone HCl

Injection, USP

CII

0.25 mg / 0.5 mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 0.5 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each 0.5 mL contains 0.25 mg hydromorphone hydrochloride, 0.12 mg of lactic acid,

2.70 mg of sodium chloride as isotonicity agent, 4.47 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA208365

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

The hydromorphone in Hydromorphone Hydrochloride 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 Hydrochloride Injection therapy.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydromorphone Hydrochloride Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non‑benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor 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 Hydrochloride Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

Hydromorphone Hydrochloride Injection may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression [see Dosage and Administration (2.1)].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE ‎OF HYDROMORPHONE HYDROCHLORIDE ‎INJECTION

See full prescribing information for complete boxed warning.

• •
  Hydromorphone Hydrochloride Injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1).
• •
  Serious, life-threatening, or fatal respiratory depression may occur with use of Hydromorphone Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and ‎titration of ‎Hydromorphone Hydrochloride Injection are essential. (5.2).
• •
  Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7).
• •
  Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4).

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 Hydrochloride Injection may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for worsening of signs of increasing intracranial pressure. Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hydromorphone Hydrochloride Injection.

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

The use of Hydromorphone Hydrochloride Injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Addiction, Abuse, and Misuse

Because use of Hydromorphone Hydrochloride Injection exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].

Safety and Handling Instructions

Access to drugs with a potential for abuse such as Hydromorphone Hydrochloride Injection presents an occupational hazard for addiction in the health care industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect health care workers. Implementation of more effective accounting procedures and measures to restrict access to drugs of this class (appropriate to the practice setting) may minimize the risk of self-administration by health care providers.

Hydromorphone Hydrochloride Injection contains hydromorphone, a substance with high potential for misuse and abuse, which can lead to the development of ‎substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than ‎‎prescribed by a healthcare provider or for ‎whom it was not prescribed.‎

Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug, use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Hydromorphone Hydrochloride Injection increases ‎risk of overdose, which may lead to ‎central nervous system and ‎respiratory depression, hypotension, seizures, and death. The risk is ‎increased with ‎concurrent abuse of Hydromorphone Hydrochloride ‎Injection with alcohol and/or other CNS ‎depressants.‎ Abuse of and addiction to opioids in some individuals may not be ‎accompanied by concurrent ‎tolerance and symptoms of physical ‎dependence. In addition, abuse of opioids can occur in the absence of ‎‎addiction.‎

All patients treated with opioids require careful and frequent reevaluation ‎for signs of misuse, abuse, and ‎addiction, because use of opioid analgesic ‎products carries the risk of addiction even under appropriate ‎medical use. ‎Patients at high risk of Hydromorphone Hydrochloride Injection abuse ‎include those with a ‎history of prolonged use of any opioid, including products containing ‎hydromorphone, those with a history of drug or alcohol abuse, ‎or those ‎who use Hydromorphone Hydrochloride Injection in combination with ‎other abused drugs.‎

"Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Hydromorphone Hydrochloride Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Hydromorphone Hydrochloride Injection is available as an aqueous sterile solution, for use in intravenous, intramuscular and subcutaneous administration, and contains hydromorphone as active pharmaceutical ingredient in the form hydrochloride salt. Hydromorphone hydrochloride is an opioid agonist.

The chemical name of hydromorphone hydrochloride is 4,5α- epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 321.8 and it has the following chemical structure.

Hydromorphone hydrochloride is a white or almost white crystalline powder that is freely soluble in water, very slightly soluble in ethanol (96%), and practically insoluble in methylene chloride.

Each mL of Hydromorphone Hydrochloride Injection sterile solution contains 0.5 mg, 1 mg or 2 mg of Hydromorphone Hydrochloride USP, equivalent to 0.44 mg, 0.89 mg or 1.77 mg of hydromorphone free base, respectively, 0.24 mg of Lactic Acid USP, 5.40 mg of Sodium Chloride as isotonicity agent, 8.93 mg of Sodium Lactate USP as buffering agent, and Lactic Acid USP and Sodium Hydroxide NF as pH adjusters, in Water for Injection. Hydromorphone Hydrochloride Injection pH range is 3.5 to 5.5.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to ‎a drug after repeated administration (i.e., a ‎higher ‎dose of a drug is ‎required to produce the same effect that was once obtained at a lower ‎dose).‎

Physical dependence is a state that develops as a result of a physiological ‎adaptation in response to repeated drug use, ‎manifested ‎by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Hydromorphone Hydrochloride Injection should not be rapidly reduced or abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6)]. If Hydromorphone Hydrochloride Injection is rapidly reduced or abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically ‎characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically-dependent on opioids will also be physically-dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Hydromorphone Hydrochloride Injection. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7)].

When discontinuing Hydromorphone Hydrochloride Injection, in a physically-dependent patient, gradually taper the dosage [see Dosage and Administration (2.6)]. Do not rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in these patients [see Drug Abuse and Dependence (9.3)].

The safety and effectiveness of Hydromorphone Hydrochloride Injection in pediatric patients has not been established.

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

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6)].

Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hydromorphone Hydrochloride Injection is contraindicated in patients with:

• •
  Significant respiratory depression [see Warnings and Precautions (5.2)]
• •
  Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)]
• •
  Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)]
• •
  Hypersensitivity to hydromorphone (e.g., anaphylaxis) [see Adverse Reactions (6)]

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

• •
  Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• •
  Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• •
  Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
• •
  Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
• •
  Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.5)]
• •
  Adrenal Insufficiency [see Warnings and Precautions (5.7)]
• •
  Severe Hypotension [see Warnings and Precautions (5.8)]
• •
  Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)]
• •
  Seizures [see Warnings and Precautions (5.11)]
• •
  Withdrawal [see Warnings and Precautions (5.12)]

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.

The most common adverse effects are light-headedness, 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.

Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Injection.

The pharmacokinetics of hydromorphone are affected by renal impairment. In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life. Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Clinical Pharmacology (12.3)].

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to ‎‎‎administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it ‎‎is ‎discolored in any other way, or if it contains a precipitate.‎

NexJect™ Single-dose Prefilled Syringe

Instructions for use – NexJect Prefilled Syringe

NOTE: To prevent needlestick injuries, do not recap, purposely bend, or break by hand used ‎needles. Do not recap, purposely bend, or break by ‎hand blunt Cannulas.

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA

LAB-1382-3.0

Revised: 12/2023

When a patient who has been taking Hydromorphone Hydrochloride Injection regularly and may be physically dependent no longer requires therapy with Hydromorphone Hydrochloride 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 rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in patients who may be physically dependent on opioids [see Warnings and Precautions (5.12), Drug Abuse and Dependence (9.3)].

Hydromorphone Hydrochloride Injection may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of Hydromorphone Hydrochloride Injection. In patients with circulatory shock, Hydromorphone Hydrochloride Injection may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Hydromorphone Hydrochloride Injection in patients with circulatory shock.

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 C_max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Clinical Pharmacology (12.3)].

Hydromorphone Hydrochloride Injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Hydromorphone is a full opioid agonist and is relatively selective for the mµ-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of hydromorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance.

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.

• •
  Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced ‎Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an ‎increase in pain, or an increase in ‎sensitivity to pain. If OIH is suspected, carefully consider appropriately ‎‎decreasing the dose of the current opioid analgesic, or ‎opioid rotation. (5.5)‎
• •
  Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. (5.6)
• •
  Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.7)
• •
  Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Hydromorphone Hydrochloride Injection in patients with circulatory shock. (5.8)
• •
  Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Hydromorphone Hydrochloride Injection in patients with impaired consciousness or coma. (5.9)

• •
  Hydromorphone Hydrochloride Injection should be ‎prescribed only by healthcare professionals who are ‎knowledgeable about the use of opioids ‎and how to ‎mitigate the associated risks. (2.1)‎
• •
  Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of Hydromorphone ‎Hydrochloride Injection for ‎patients in whom lower doses are insufficiently ‎effective and in whom the expected benefits of using a higher dose opioid ‎clearly outweigh ‎the substantial risks. (2.1, 5)
• •
  Many acute pain conditions (e.g., the pain that occurs with ‎a number of surgical procedures or acute ‎musculoskeletal injuries) require no more ‎than a few ‎days of an opioid analgesic. Clinical guidelines on ‎opioid prescribing for some acute pain conditions are ‎available. (2.1)
• •
  Initiate the dosing regimen for each patient individually, ‎taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. (2.1, 5.1)
• •
  Respiratory depression can occur at any time during opioid ‎therapy, especially when initiating and following dosage ‎increases with ‎Hydromorphone Hydrochloride Injection. ‎Consider this risk when selecting an initial dose and when ‎making dose adjustments. (2.1, 5.2)‎
• •
  Intramuscular and Subcutaneous Use: The usual starting dose is 1 mg to 2 mg every 2 to 3 hours as necessary. (2.2)
• •
  Intravenous Use: The usual starting dose is 0.2 mg to 1 mg every 2 to 3 hours. The injection should be given slowly, over at least 2 to 3 minutes. (2.2)
• •
  Hepatic Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of hepatic impairment. (2.3)
• •
  Renal Impairment: Initiate treatment with one-fourth to one-half the usual starting dose, depending on degree of renal impairment. (2.4)
• •
  Periodically reassess patients receiving Hydromorphone Hydrochloride Injection to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. (2.5)
• •
  Do not rapidly reduce or abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient. (2.6, 5.12)

Hydromorphone Hydrochloride Injection, USP is available as:

The drug product is a clear, colorless to nearly colorless aqueous sterile solution. Each 1 mL of sterile solution contains 0.5 mg, 1 mg or 2 mg of hydromorphone hydrochloride.

• •
  Pregnancy: May cause fetal harm. (8.1)
• •
  Geriatric Patients: Use caution during dose selection, starting at the low ‎end of the dosing range while carefully monitoring for side effects. ‎‎(8.5)

Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Injection exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Hydromorphone Hydrochloride Injection. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6)].

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Hydromorphone Hydrochloride Injection, and monitor all patients receiving Hydromorphone Hydrochloride 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 Hydrochloride Injection but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Injection along with intensive monitoring for signs of addiction, abuse, and misuse.

Opioids are sought for nonmedical use and are subject to diversion from ‎legitimate prescribed use. Consider these risks when prescribing or dispensing Hydromorphone Hydrochloride 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.

Use of Hydromorphone Hydrochloride Injection for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations (8.1)].

Titrate the dose based upon the individual patient’s response to their initial dose of Hydromorphone Hydrochloride Injection. Individually titrate Hydromorphone Hydrochloride Injection to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Hydromorphone Hydrochloride Injection to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1, 5.12)]. 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 Hydrochloride Injection dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5)]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

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 overdose reversal agent (e.g., naloxone, nalmefene), depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Hydromorphone Hydrochloride Injection, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential [see Dosage and Administration (2.1)]. Overestimating the Hydromorphone Hydrochloride Injection dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.1)].

Hydromorphone Hydrochloride Injection is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The hydromorphone in Hydromorphone Hydrochloride 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.

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

Hydromorphone Hydrochloride 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 Hydrochloride Injection and know how they will react to the medication.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic ‎paradoxically causes an increase in pain, or an ‎increase in sensitivity to pain. ‎This condition differs from tolerance, which is the need for increasing doses of ‎opioids to ‎maintain a defined effect [Drug Abuse and Dependence (9.3)]. Symptoms of OIH ‎include (but may not be limited to) increased levels ‎of pain upon opioid dosage ‎increase, decreased levels of pain upon opioid dosage decrease, or pain from ‎ordinarily non‑‎painful stimuli (allodynia). These symptoms may suggest OIH only ‎if there is no evidence of underlying disease ‎progression, opioid tolerance, ‎opioid withdrawal, or addictive behavior.‎

Cases of OIH have been reported, both with short-term and longer-term use of ‎opioid analgesics. Though the ‎mechanism of OIH is not fully understood, ‎multiple biochemical pathways have been implicated. Medical literature ‎suggests ‎a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a ‎patient is suspected to be experiencing OIH, ‎carefully consider appropriately ‎decreasing the dose of the current opioid analgesic or opioid rotation (safely ‎switching ‎the patient to a different opioid moiety) [see Dosage and ‎Administration (2.6), Warnings and Precautions (5.12)].‎

HYDROmorphone HCl

Injection, USP

PAA140442

CII

1 mg/mL

HYDROmorphone HCl

Injection, USP

PAA140441

CII

2 mg/mL

• •
  Hydromorphone Hydrochloride Injection should be prescribed only by healthcare ‎professionals who are knowledgeable about the use of opioids and how to ‎mitigate the associated risks.
• •
  Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because ‎the risk of overdose increases as opioid doses increase, reserve titration to ‎higher doses of Hydromorphone Hydrochloride Injection for patients in whom ‎lower doses are insufficiently effective and in whom the expected benefits of ‎using a higher dose opioid clearly outweigh the substantial risks.‎
• •
  Many acute pain conditions (e.g., the pain that occurs with a number of surgical ‎procedures or acute musculoskeletal injuries) require no more than a few days ‎of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute ‎pain conditions are available.
• •
  There is variability in the opioid analgesic dose and duration needed to ‎adequately manage pain due both to the cause of pain and to individual patient ‎factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1)].
• •
  Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydromorphone Hydrochloride Injection. Consider this risk when selecting an initial dose and ‎when making dose adjustments [see Warnings and Precautions (5)].
• •
  Inspect Hydromorphone Hydrochloride Injection for particulate matter and discoloration prior to administration. A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection. No loss of potency has been demonstrated. Hydromorphone Hydrochloride Injection is 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.

HYDROmorphone HCl

Injection, USP

PAA152907

CII

0.5 mg/0.5 mL

HYDROmorphone HCl

Injection, USP

PAA208366

CII

0.25 mg/0.5 mL

TWIST & PULL

Tamper Seal

NDC 0409-1283-17

CII

HYDROmorphone HCl

Injection, USP

1 mg/mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

1 mL Single-dose syringe

PAA140444

LOT #####AA

EXP DMMMYYYY

TWIST & PULL

Tamper Seal

NDC 0409-1312-16

CII

HYDROmorphone HCl

Injection, USP

2 mg/mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

1 mL Single-dose syringe

PAA140445

LOT #####AA

EXP DMMMYYYY

Start patients with renal impairment on one-fourth to one-half the usual starting dose of Hydromorphone Hydrochloride Injection depending on the degree of impairment [see Clinical Pharmacology (12.3)].

NDC 0409-1283-37

HYDROmorphone HCl

Injection, USP

CII

1 mg / mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 1 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each mL contains 1 mg hydromorphone hydrochloride, 0.24 mg of lactic acid,

5.40 mg sodium chloride as isotonicity agent, 8.93 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211792

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

NDC 0409-1312-36

HYDROmorphone HCl

Injection, USP

CII

2 mg / mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 1 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each mL contains 2 mg hydromorphone hydrochloride, 0.24 mg of lactic acid,

5.40 mg sodium chloride as isotonicity agent, 8.93 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211791

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

Start patients with hepatic impairment on one-fourth to one-half the usual dose of Hydromorphone Hydrochloride Injection depending on the extent of impairment [see Clinical Pharmacology (12.3)].

TWIST & PULL

Tamper Seal

NDC 0409-4264-11

CII

HYDROmorphone HCl

Injection, USP

0.5 mg/0.5 mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

0.5 mL Single-dose syringe

PAA152909

LOT #####AA

EXP DMMMYYYY

TWIST & PULL

Tamper Seal

NDC 0409-1805-10

CII

HYDROmorphone HCl

Injection, USP

0.25 mg/0.5 mL

Intravenous, Intramuscular,

or Subcutaneous Use

Protect from light

Rx only

0.5 mL Single-dose syringe

PAA208364

LOT AA####

EXP YYYY / MM

NDC 0409-4264-01

HYDROmorphone HCl

Injection, USP

CII

0.5 mg / 0.5 mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 0.5 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each 0.5 mL contains 0.5 mg hydromorphone hydrochloride, 0.12 mg of lactic acid,

2.70 mg sodium chloride as isotonicity agent, 4.47 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA211659

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

NDC 0409-1805-01

HYDROmorphone HCl

Injection, USP

CII

0.25 mg / 0.5 mL

For Intravenous, Intramuscular, or Subcutaneous Use

10 NexJect™ 0.5 mL Single-dose syringes with luer lock

Rx only

Needle not included

Protect from light. Opaque covering needed until contents are used.

Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

Sterile Aqueous Injection

Usual Dosage: See Package Insert.

Each 0.5 mL contains 0.25 mg hydromorphone hydrochloride, 0.12 mg of lactic acid,

2.70 mg of sodium chloride as isotonicity agent, 4.47 mg of sodium lactate as a

buffering agent and lactic acid and sodium hydroxide as pH adjusters.

Do not use if solution is discolored or contains a precipitate.

PAA208365

Distributed by Hospira, Inc.

Lake Forest, IL 60045 USA

Hospira

The hydromorphone in Hydromorphone Hydrochloride 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 Hydrochloride Injection therapy.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Hydromorphone Hydrochloride Injection with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non‑benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor 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 Hydrochloride Injection is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].

Hydromorphone Hydrochloride Injection may be given intravenously, but the injection should be given very slowly. Rapid intravenous injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression [see Dosage and Administration (2.1)].

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE ‎OF HYDROMORPHONE HYDROCHLORIDE ‎INJECTION

See full prescribing information for complete boxed warning.

• •
  Hydromorphone Hydrochloride Injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. (5.1).
• •
  Serious, life-threatening, or fatal respiratory depression may occur with use of Hydromorphone Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and ‎titration of ‎Hydromorphone Hydrochloride Injection are essential. (5.2).
• •
  Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. (5.3, 7).
• •
  Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. (5.4).

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 Hydrochloride Injection may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure. Monitor such patients for worsening of signs of increasing intracranial pressure. Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy with Hydromorphone Hydrochloride Injection.

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

The use of Hydromorphone Hydrochloride Injection in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.