DILAUDID

DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid agonist. DILAUDID INJECTION 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 DILAUDID 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 DILAUDID (hydromorphone hydrochloride) include: 0.2% sodium citrate and 0.2% citric acid added as a buffer to maintain a pH between 3.5 and 5.5. dilau-struc-01.jpg

DILAUDID 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: ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve Hydromorphone Hydrochloride Injection for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): • Have not been tolerated, or are not expected to be tolerated • Have not provided adequate analgesia or are not expected to provide adequate analgesia DILAUDID INJECTION should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. DILAUDID INJECTION is indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use: Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.1 )] , reserve DILAUDID INJECTION for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): • Have not been tolerated or are not expected to be tolerated, • Have not provided adequate analgesia or are not expected to provide adequate analgesia. DILAUDID INJECTION should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

• DILAUDID 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 ) • Do not abruptly discontinue DILAUDID INJECTION in a physically-dependent patient. ( 2.6 , 5.12 ) 2.1 Important Dosage and Administration Instructions • DILAUDID 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 DILAUDID 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 DILAUDID INJECTION. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )] . • Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in DILAUDID INJECTION. No loss of potency has been demonstrated. DILAUDID 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 DILAUDID INJECTION as the First Opioid Analgesic: Subcutaneous or Intramuscular Administration: The usual starting dose is 1 mg to 2 mg every 2 to 3 hours as necessary for pain, and 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: The initial starting dose is 0.2 mg to 1 mg every 2 to 3 hours. Intravenous administration should be given slowly , over at least 2 to 3 minutes, depending on the dose. The initial dose should be reduced in the elderly or debilitated and may be lowered to 0.2 mg. Conversion From Other Opioids to DILAUDID 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 DILAUDID INJECTION. It is safer to underestimate a patient's 24-hour DILAUDID INJECTION dosage than to overestimate the 24-hour DILAUDID 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 DILAUDID 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 DILAUDID INJECTION starting dose 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 DILAUDID INJECTION starting dose 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 DILAUDID INJECTION. Individually titrate DILAUDID INJECTION to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving DILAUDID INJECTION to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as monitoring 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 DILAUDID 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 or Discontinuation of DILAUDID INJECTION When a patient who has been taking DILAUDID INJECTION regularly and may be physically dependent no longer requires therapy with DILAUDID INJECTION, taper the dose gradually, by 25% to 50% every 2 to 4 days, while monitoring carefully for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not abruptly discontinue DILAUDID INJECTION in a physically-dependent patient [see Warnings and Precautions ( 5.12 ), Drug Abuse and Dependence ( 9.3 )].

DILAUDID 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, 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 )

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 DILAUDID 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. 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 DILAUDID INJECTION. Androgen deficiency : Cases of androgen deficiency have occurred with 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 least one predisposing risk factor (e.g., diabetes).

Table 1 includes clinically significant drug interactions with DILAUDID INJECTION. Table 1. Clinically Significant Drug Interactions with DILAUDID 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 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 [see Warnings and Precautions ( 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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 DILAUDID 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 DILAUDID 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 DILAUDID 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 DILAUDID INJECTION and/or the muscle relaxant as necessary. 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 DILAUDID INJECTION is used concomitantly with anticholinergic drugs. • Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue DILAUDID 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 DILAUDID INJECTION because they may reduce analgesic effect of DILAUDID INJECTION or precipitate withdrawal symptoms. ( 7 )