Hydromorphone Hydrochloride

1 INDICATIONS AND USAGE Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is indicated for use in opioid-tolerant patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Patients considered opioid tolerant are those who are taking for one week or longer, around-the-clock medicine consisting of at least 60 mg oral morphine per day, or at least 25 mcg transdermal fentanyl per hour, or at least 30 mg oral oxycodone per day, or at least 8 g oral hydromorphone per day, or at least 25 mg oral oxymorphone per day, or at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid for one week or longer. Patients must remain on around-the-clock opioids while administering Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]. Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is an opioid agonist indicated for use in opioid-tolerant patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Patients considered opioid tolerant are those who are taking, for one week or longer, around-the-clock medicine consisting of at least 60 mg of oral morphine per day, at least 25 mcg/hr of transdermal fentanyl per hour, at least 30 mg of oral oxycodone per day, at least 8 mg of oral hydromorphone per day, at least 25 mg oral oxymorphone per day, at least 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid daily for a week or longer. Patients must remain on around-the-clock opioids when administering Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]. 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 [high potency formulation (HPF)], 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 , 5.2 ) 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 (5.2) ] , reserve opioid analgesics, including Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

2 DOSAGE AND ADMINISTRATION • Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 [high potency formulation (HPF)] 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 , 5.2 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.3 ) • 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 ) • Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is for opioid-tolerant patients only and should be used only if the amount of hydromorphone required can be delivered accurately with this formulation. ( 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 [HPF] 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 [high potency formulation (HPF)] in a physically-dependent patient. ( 2.6, 5.13 ) 2.1 Important Dosage and Administration Instructions • Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 [high potency formulation (HPF)] 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, t…

5 WARNINGS AND PRECAUTIONS • 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. ( 5.6 ) • Life-Threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, particularly during initiation and titration. ( 5.7 ) • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.8 ) • Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] in patients with circulatory shock. ( 5.9 ) • 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 [high potency formulation (HPF)] in patients with impaired consciousness or coma. ( 5.10 ) 5.1 Risk of Medication Errors Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is a 10 mg/mL concentrated solution of hydromorphone, and is intended for use in opioid-tolerant patients only. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine/day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day, or an equianalgesic dose of another opioid for one week or longer. Do not confuse Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] with standard parenteral formulations of Hydromorphone Hydrochloride Injection, or other opioids as overdose and death could result. 5.2 Addiction, Abuse, and Misuse Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] contain hydromorphone, a Schedule II controlled substance. As an opioid, Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 [high potency formulation (HPF)]. 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 [high potency formulation (HPF)], and monitor all patients receiving Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 [high potency formulation (HPF)], but use in such patients necessitates intensive counseling about the risks and proper use of Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 H…

4 CONTRAINDICATIONS Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.3) ] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.7) ] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.11) ] • Hypersensitivity to hydromorphone, hydromorphone salts, or any other components of the product (e.g., anaphylaxis) [see Adverse Reactions (6) ] . Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] is contraindicated in patients who are not opioid tolerant [see Warnings and Precautions (5.1) ] . • 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, or any other components of the product. ( 4 ) • Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]: Patients who are not opioid tolerant. ( 4 )

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Hydromorphone Hydrochloride Injection [high potency formulation (HPF)]. Table 1. Clinically Significant Drug Interactions with Hydromorphone Hydrochloride Injection [high potency formulation (HPF)] 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 Warnings and Precautions (5.4) ] . 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 (5.4) ] . 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 [high potency formulation (HPF)] 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 (5.3) ] . 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 [high potency formulation (HPF)] 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 [high potency formulation (HPF)] 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 [high potency formulation (HPF)] 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 Drug…

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 (5.5) ] . 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 (5.5) ] . 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 [high potency formulation (HPF)] 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 [high potency formulation (HPF)], 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 surf…

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 (5.2) ] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3) ] • Interactions With Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4) ] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5) ] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.6) ] • Adrenal Insufficiency [see Warnings and Precautions (5.8) ] • Severe Hypotension [see Warnings and Precautions (5.9) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.11) ] • Seizures [see Warnings and Precautions (5.12) ] • Withdrawal [see Warnings and Precautions (5.13) ] 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 [high potency formulation (HPF)] 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. Most common adverse reactions are lightheadedness, dizziness, sedation, nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. ( 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, 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 [high potency formulation (HPF)]. Androgen deficiency : Cases of androgen deficiency …