HYDROMORPHONE HYDROCHLORIDE

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. Chemical Structure

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 Hydrochloride Injection is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use : Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Hydromorphone Hydrochloride Injection, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 ) Limitations of Use Because of the risks of addiction, abuse, misuse , overdose, and death , which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ] , reserve opioid analgesics, including Hydromorphone Hydrochloride Injection , for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• Hydromorphone Hydrochloride 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 ) 2.1 Important Dosage and Administration Instructions • 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. 2.2 Initial Dosage Use of Hydromorphone Hydrochloride Injection as the First Opioid Analgesic Subcutaneous or Intramuscular Administration Initiate treatment in a dosing range of 1 mg to 2 mg every 2 to 3 hours as necessary for pain, and at the lowest dose necessary to achieve adequate analgesia. Depending on the clinical situation, the initial starting dose may be lowered in patients who are opioid naïve. Titrate the dose based upon the individual patient’s response to their initial dose ‎of Hydromorphone ‎Hydrochloride Injection.‎ Intravenous Administration Initiate treatment in a dosing range of 0.2 mg to 1 mg every 2 to 3 hours as necessary for pain control, and at the lowest dose necessary to achieve adequate analgesia. Intravenous administration should be given slowly, over at least 2 to 3 minutes, depending on the dose. Titrate the dose to achieve acceptable pain management and tolerable adverse events. 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 Hydrochloride 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 Hydrochloride Injection. It is safer to underestimate a patient's 24-hour Hydromorphone Hydrochloride Injection dosage than to overestimate the 24-hour Hydromorphone Hydrochloride 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 Hydrochloride 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. 2.3 Dosage Modifications in Patients with Hepatic Impairment 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) ] . 2.4 Dosage Modifications in Patients with Renal Impairment 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) ]. 2.5 Titration and Maintenance of Therapy 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. 2.6 Safe Reduction and Discontinuation of Hydromorphone Hydrochloride Injection 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 patient s who may be physically dependent on opioids [see Warnings and Precautions (5.12) , Drug Abuse and Dependence (9.3) ] .

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) ] • Significant respiratory depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Known hypersensitivity to hydromorphone. ( 4 )

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. Most common adverse reactions are light-headedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. Serious adverse reactions include respiratory depression and apnea, circulatory depression, respiratory arrest, shock and cardiac arrest. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch . 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 Hepatobiliary disorders : biliary colic 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 Psychiatric disorders : agitation, mood altered, nervousness, anxiety, depression, hallucination, disorientation, insomnia, abnormal dreams Renal and urinary disorders : urinary retention, urinary hesitation, antidiuretic effects Respiratory, thoracic and mediastinal disorders : bronchospasm, laryngospasm 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 Hydrochloride Injection. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been ‎reported with opioid therapy of ‎any duration. [see Warnings and Precautions ‎‎(5.5) ]‎. Hypoglycemia : Cases of hypoglycemia have been reported in patients ‎taking opioids. Most reports were in ‎patients with at least one ‎predisposing risk factor (e.g., diabetes).‎ Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.10) ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2) ] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose‑related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Injection. Table 1: Clinically Significant Drug Interactions with Hydromorphone Hydrochloride Injection Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor patients closely for signs of respiratory depression and sedation. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Hydromorphone Hydrochloride Injection if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. Intervention: The use of Hydromorphone Hydrochloride Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Hydromorphone Hydrochloride Injection and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydromorphone Hydrochloride Injection and/or the muscle relaxant as necessary. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when Hydromorphone Hydrochloride Injection is used concomitantly with anticholinergic drugs. • Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue Hydromorphone Hydrochloride Injection if serotonin syndrome is suspected. ( 7 ) • Monoamine Oxidase Inhibitors (MAOIs) : Can potentiate the effects of hydromorphone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 ) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Hydromorphone Hydrochloride Injection because they may reduce analgesic effect of Hydromorphone Hydrochloride Injection or precipitate withdrawal symptoms. ( 7 )

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. Note that a needle is not included. PROTECT FROM LIGHT Keep covered in carton until time of use. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].