Hydromorphone Hydrochloride

RECENT MAJOR CHANGES Boxed Warning...................................................................12/2023 Indications and Usage (1)........................................................12/2023 Dosage and Administration (2.1, 2.2, 2.5)....................................12/2023 Warnings and Precaution (5.5)...................................................12/2023 Boxed Warning...................................................................12/2025 Indications and Usage ( 1 )......................................................12/2025 Dosage and Administration ( 2.6 )...............................................12/2025 Warnings and Precaution ( 5.1 , 5.2 , 5.3 , 5.10 , 5.12 )......................12/2025

1 INDICATIONS AND USAGE Hydromorphone hydrochloride injection is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitation 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 (5.2) ] , 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 is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternate 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 )

2 DOSAGE AND ADMINISTRATION 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 of time 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 ) Initial Dosage: Intramuscular or 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 of 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 Warning …

3 DOSAGE FORMS AND STRENGTHS Hydromorphone Hydrochloride Injection, USP: Each single-dose prefilled syringe contains 0.2 mg/mL, 0.5 mg/0.5 mL, 1 mg/mL or 2 mg/mL of hydromorphone hydrochloride in a sterile, aqueous solution. Hydromorphone Hydrochloride Injection, USP, 0.2 mg/mL, 0.5 mg/0.5mL, 1 mg/mL or 2 mg/mL are available in single-dose prefilled syringes. ( 3 )

4 CONTRAINDICATIONS 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, hydromorphone salts, or any other components of the product, or sulfite containing medications (e.g., anaphylaxis) [see Warnings and Precautions (5.14) ] 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, hydromorphone salts, sulfite containing medications, or any other components of the product ( 4 )

6 ADVERSE REACTIONS 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 and 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. Serious adverse reactions associated with hydromorphone hydrochloride injection include respiratory depression and apnea and, to a lesser degree, circulatory depression, respiratory arrest, shock, and cardiac arrest. The most common adverse effects are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. These effects seem to be more prominent in ambulatory patients and in those not experiencing severe pain. Less Frequently Observed Adverse Reactions Cardiac disorders: tachycardia, bradycardia, palpitations Eye disorders: vision blurred, diplopia, miosis, visual impairment Gastrointestinal disorders: constipation, ileus, diarrhea, abdominal pain General disorders and administration site conditions: weakness, feeling abnormal , chills, injection site urticaria, fatigue, injection site reactions, peripheral edema Hepatobiliary disorders: biliary colic Immune system disorders: anaphylactic reactions, hypersensitivity reactions Investigations: hepatic enzymes increased Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: muscle rigidity Nervous system disorders: headache, tremor, paraesthesia, nystagmus, increased intracranial pressure, syncope, taste alteration , involuntary muscle contractions, presyncope, convulsion, drowsiness, dyskinesia, hyperalgesia, lethargy, myoclonus, somnolence Psychiatric disorders: agitation, mood altered, nervousness, anxiety , depression, hallucination, disorientation, insomnia, abnormal dreams Renal and urinary disorders: urinary retention, urinary hesitation, antidiuretic effects Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic, and mediastinal disorders: bronchospasm, laryngospasm, dyspnea, oropharyngeal swelling Skin and subcutaneous tissue disorders: injection site pain, urticaria, rash, hyperhidrosis Vascular disorders: flushing, hypotension, hypertension Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in hydromorphone hydrochloride injection. Androgen deficiency : Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time [see CLINICAL PHARMACOLOGY (12.2) ] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.5) ] Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at le …

7 DRUG INTERACTIONS 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 Depressants (CNS) Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. [see Warni ngs 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 [see Warnings and Precautions (5.3) ] . 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) ] . 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. 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 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 syndrome. 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 fo …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ] . There are no available data with hydromorphone hydrochloride injection in pregnant women to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations). In animal reproduction studies, reduced postnatal survival of pups, and decreased body weight were noted following oral treatment of pregnant rats with hydromorphone during gestation and through lactation at doses 0.8 times the human daily dose of 24 mg/day (HDD), respectively. In published studies, neural tube defects were noted following subcutaneous injection of hydromorphone to pregnant hamsters at doses 6.4 times the HDD and soft tissue and skeletal abnormalities were noted following subcutaneous continuous infusion of 3 times the HDD to pregnant mice. No malformations were noted at 4 or 40.5 times the HDD in pregnant rats or rabbits, respectively [ see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydromorphone hydrochloride injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including hydromorphone hydrochloride injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data Pregnant rats were treated with hydromorphone hydrochloride from Gestation Day 6 to 17 via oral gavage doses of 1, 5, or 10 mg/kg/day (0.4, 2, or 4 times the HDD of 24 mg based on body surface area, respectively). Maternal toxicity was noted in all treatment groups (reduced food consumption and body weights in the two highest dose groups). There was no evidence of malformations or embryotoxicity reported. Pregnant rabbits were treated with hydromorphone hydrochloride from Gestation Day 7 to 19 via oral gavage doses of 10, 25, or 50 mg/kg/day (8.1, 20.3, or 40.5 times the HDD of 24 mg based on body su …

12.1 Mechanism of Action Hydromorphone is a full opioid agonist and is relatively selective for the mu-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.

11 DESCRIPTION Hydromorphone Hydrochloride, a hydrogenated ketone of morphine, is an opioid agonist. Hydromorphone Hydrochloride Injection, USP is available as a sterile, aqueous solution in clear and colorless single-dose prefilled syringes for slow intravenous, subcutaneous, or intramuscular administration. Each 1 mL of solution contains 0.2 mg, 1 mg or 2 mg of hydromorphone hydrochloride. The chemical name of Hydromorphone Hydrochloride is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 321.80. Its molecular formula is C 17 H 19 NO 3 ·HCl, 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. The inactive ingredients in Hydromorphone Hydrochloride Injection, USP include: 0.2% sodium citrate and 0.2% citric acid added as a buffer to maintain a pH between 3.5 and 5.5. structure

OVERDOSAGE SIGNS AND SYMPTOMS Serious overdosage with hydromorphone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest and death may occur. It is difficult to determine what constitutes a standard toxic or lethal dose. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates. TREATMENT Primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including hydromorphone. Therefore, an appropriate dose of naloxone hydrochloride should be administered, preferably by the intravenous route in conjunction with ventilatory assistance. Since the duration of action of hydromorphone may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. The patient should be closely observed for a rise in temperature or pulmonary complications that may signal the need for institution of antibiotic therapy. NOTE: In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will depend on the degree of physical dependence and the dose of antagonist administered. The use of narcotic antagonists in such individuals should be avoided if possible. If a narcotic antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and only one-tenth to one-fifth the usual initial dose administered.

16 HOW SUPPLIED/STORAGE AND HANDLING Hydromorphone Hydrochloride Injection, USP is supplied in clear and colorless single-dose prefilled syringes. Each single-dose prefilled syringe of sterile, aqueous solution contains 0.2 mg, 0.5 mg, 1 mg or 2 mg hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid solution. Hydromorphone Hydrochloride Injection, USP contains no added preservative and is supplied as follows: Unit of Sale Strength Each NDC 0641-6259-10 Unit of 10 0.2 mg/mL 1 mL single-dose prefilled syringe NDC 0641-6206-10 Unit of 10 0.5 mg/0.5 mL 0.5 mL single-dose prefilled syringe NDC 0641-6169-10 Unit of 10 1 mg/mL 1 mL single-dose prefilled syringe NDC 0641-6170-10 Unit of 10 2 mg/mL 1 mL single-dose prefilled syringe PROTECT FROM LIGHT. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Safety and Handling Instructions Discard any unused portion. Access to drugs with a potential for abuse such as Hydromorphone Hydrochloride Injection, USP 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.