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| Product NDC Code | 0409-1312 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Hydromorphone hydrochloride |
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| Type | Generic | ||||||
| Pharm Class | Full Opioid Agonists [MoA], Opioid Agonist [EPC] |
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| Active Ingredients |
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| Route | INTRAMUSCULAR, INTRAVENOUS, SUBCUTANEOUS | ||||||
| Dosage Form | INJECTION, SOLUTION | ||||||
| RxCUI drug identifier | 897653, 897753, 897756, 897757, 897758, 1433251, 1724276, 1724383, 1724644 |
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| Application Number | NDA200403 | ||||||
| Labeler Name | Hospira, Inc. | ||||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
Abuse
Information about the types of abuse that can occur with the drug and adverse reactions pertinent to those types of abuse, primarily based on human data. May include descriptions of particularly susceptible patient populations.9.2 Abuse Hydromorphone Hydrochloride Injection contains hydromorphone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug, use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Hydromorphone Hydrochloride Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Hydromorphone Hydrochloride Injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Hydromorphone Hydrochloride Injection abuse include those with a history of prolonged use of any opioid, including products containing hydromorphone, those with a history of drug or alcohol abuse, or those who use Hydromorphone Hydrochloride Injection in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Hydromorphone Hydrochloride Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Hydromorphone Hydrochloride Injection Abuse of Hydromorphone Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent use of Hydromorphone Hydrochloride Injection with alcohol and/or other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
Controlled substance
Information about the schedule in which the drug is controlled by the Drug Enforcement Administration, if applicable.9.1 Controlled Substance Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance.
Dependence
Information about characteristic effects resulting from both psychological and physical dependence that occur with the drug, the quantity of drug over a period of time that may lead to tolerance or dependence, details of adverse effects related to chronic abuse and the effects of abrupt withdrawl, procedures necessary to diagnose the dependent state, and principles of treating the effects of abrupt withdrawal.9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Hydromorphone Hydrochloride Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6) ]. If Hydromorphone Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .
Drug abuse and dependence
Information about whether the drug is a controlled substance, the types of abuse that can occur with the drug, and adverse reactions pertinent to those types of abuse.9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Hydromorphone Hydrochloride Injection contains hydromorphone, a Schedule II controlled substance. 9.2 Abuse Hydromorphone Hydrochloride Injection contains hydromorphone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug, use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Hydromorphone Hydrochloride Injection increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Hydromorphone Hydrochloride Injection with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Hydromorphone Hydrochloride Injection abuse include those with a history of prolonged use of any opioid, including products containing hydromorphone, those with a history of drug or alcohol abuse, or those who use Hydromorphone Hydrochloride Injection in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating health care provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Hydromorphone Hydrochloride Injection, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Hydromorphone Hydrochloride Injection Abuse of Hydromorphone Hydrochloride Injection poses a risk of overdose and death. The risk is increased with concurrent use of Hydromorphone Hydrochloride Injection with alcohol and/or other CNS depressants. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Hydromorphone Hydrochloride Injection should not be abruptly discontinued in a physically-dependent patient [see Dosage and Administration (2.6) ]. If Hydromorphone Hydrochloride Injection is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ] .
Overdosage of HYDROMORPHONE HYDROCHLORIDE
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Clinical Presentation Acute overdose with hydromorphone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to hydromorphone overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of hydromorphone in Hydromorphone Hydrochloride Injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product's prescribing information. In an individual physically-dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically-dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.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 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 Hospira, Inc. at 1-800-441-4100 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 disorder s: 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).
HYDROMORPHONE HYDROCHLORIDE Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.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 (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of 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, 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. 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 )
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Hydromorphone is a full opioid agonist and is relatively selective for the mµ-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of hydromorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on the Central Nervous System Hydromorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Hydromorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of hydromorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing hydromorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.5 )] . 12.3 Pharmacokinetics Distribution At therapeutic plasma levels, hydromorphone is approximately 8–19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 (32%) liters. Elimination The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours. Metabolism Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Excretion Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Specific Populations Hepatic Impairment After oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets), mean exposure to hydromorphone (C max and AUC ∞ ) is increased 4 fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in C max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Use in Specific Populations (8.6) ]. Renal Impairment The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (C max and AUC 0–∞ ) is increased by 2 fold in patients with moderate (CLcr = 40 – 60 mL/min) renal impairment and increased by 4 fold in patients with severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Use in Specific Populations (8.7) ]. Age: Geriatric Population In the geriatric population, age has no effect on the pharmacokinetics of hydromorphone. Sex Sex has little effect on the pharmacokinetics of hydromorphone. Females appear to have a higher C max (25%) than males with comparable AUC 0–24 values. The difference observed in C max may not be clinically relevant.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Hydromorphone is a full opioid agonist and is relatively selective for the mµ-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of hydromorphone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Effects on the Central Nervous System Hydromorphone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Hydromorphone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon [see Adverse Reactions (6) ] . Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of hydromorphone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.5) ] . Concentration–Adverse Reaction Relationships There is a relationship between increasing hydromorphone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.5 )] .
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics Distribution At therapeutic plasma levels, hydromorphone is approximately 8–19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume of distribution [mean (%cv)] is 302.9 (32%) liters. Elimination The systemic clearance is approximately 1.96 (20%) liters/minute. The terminal elimination half-life of hydromorphone after an intravenous dose is about 2.3 hours. Metabolism Hydromorphone is extensively metabolized via glucuronidation in the liver, with greater than 95% of the dose metabolized to hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Excretion Only a small amount of the hydromorphone dose is excreted unchanged in the urine. Most of the dose is excreted as hydromorphone-3-glucuronide along with minor amounts of 6-hydroxy reduction metabolites. Specific Populations Hepatic Impairment After oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets), mean exposure to hydromorphone (C max and AUC ∞ ) is increased 4 fold in patients with moderate (Child-Pugh Group B) hepatic impairment compared with subjects with normal hepatic function. Patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in C max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Use in Specific Populations (8.6) ]. Renal Impairment The pharmacokinetics of hydromorphone following an oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone immediate-release tablets) are affected by renal impairment. Mean exposure to hydromorphone (C max and AUC 0–∞ ) is increased by 2 fold in patients with moderate (CLcr = 40 – 60 mL/min) renal impairment and increased by 4 fold in patients with severe (CLcr < 30 mL/min) renal impairment compared with normal subjects (CLcr > 80 mL/min). In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration [see Use in Specific Populations (8.7) ]. Age: Geriatric Population In the geriatric population, age has no effect on the pharmacokinetics of hydromorphone. Sex Sex has little effect on the pharmacokinetics of hydromorphone. Females appear to have a higher C max (25%) than males with comparable AUC 0–24 values. The difference observed in C max may not be clinically relevant.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.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 (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 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Hydromorphone Hydrochloride Injection is an opioid agonist and available as an aqueous sterile solution, for use for intravenous, intramuscular and subcutaneous administration. It contains hydromorphone as active pharmaceutical ingredient in the form of hydrochloride salt. 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 1 mg, 2 mg, or 4 mg of Hydromorphone Hydrochloride USP, equivalent to 0.89 mg, 1.77 mg or 3.55 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
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.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 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 ) • Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. ( 2.1 ) • 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 ) • Do not abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient. ( 2.6 ) 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 experience, 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 of 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 (5.2) ]. • Inspect Hydromorphone Hydrochloride for particulate matter and discoloration prior to administration. Do not use if there is any discoloration or precipitate. A slight yellowish discoloration may develop in Hydromorphone Hydrochloride Injection ampuls. 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 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 abruptly discontinue Hydromorphone Hydrochloride Injection in a physically-dependent patient [see Warnings and Precautions (5.12) , Drug Abuse and Dependence (9.3) ] .
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Hydromorphone Hydrochloride Injection, USP is available as: • Single-dose Ampuls • Single-dose Carpuject™ cartridges • Single-dose iSecure™ Syringes • Single-dose Vials 1 mg/mL, 2 mg/mL, and 4 mg/mL 1 mg/mL, 2 mg/mL, and 4 mg/mL 0.5 mg/0.5 mL, 1 mg/mL, and 2 mg/mL 2 mg/mL The drug product is a clear, colorless to nearly colorless aqueous sterile solution. Each 1 mL of sterile solution contains 1 mg, 2 mg or 4 mg of hydromorphone hydrochloride. Injection: 0.5 mg/0.5 mL, 1 mg/mL, 2 mg/mL and 4 mg/mL is available in single-dose ampuls, single-dose Carpuject™ cartridges with Luer Lock for use with the Carpuject™ Syringe System, single-dose iSecure™ prefilled syringes with Luer Lock, and single-dose vials for parenteral administration. ( 3 )
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Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE 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: ( 1 ) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration ( 5.1 ), 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. Hydromorphone Hydrochloride 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. 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 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. Hydromorphone Hydrochloride 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.
Spl product data elements
Usually a list of ingredients in a drug product.Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE Hydromorphone Hydrochloride HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE HYDROCHLORIDE HYDROMORPHONE SODIUM LACTATE SODIUM CHLORIDE LACTIC ACID, UNSPECIFIED FORM SODIUM HYDROXIDE
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of hydromorphone have not been conducted. Mutagenesis Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay. Impairment of Fertility No effects on fertility, reproductive performance, or reproductive organ morphology were observed in male or female rats given oral doses up to 7 mg/kg/day which is 2.8 times the human dose of 24 mg hydromorphone hydrochloride injection (4 mg every 4 hours), on a body surface area basis.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of hydromorphone have not been conducted. Mutagenesis Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay. Impairment of Fertility No effects on fertility, reproductive performance, or reproductive organ morphology were observed in male or female rats given oral doses up to 7 mg/kg/day which is 2.8 times the human dose of 24 mg hydromorphone hydrochloride injection (4 mg every 4 hours), on a body surface area basis.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 1 mg/mL Ampule Label RL - 4950 NDC 0409-2552-11 Rx only 1 mL Single-use ampul HYDROmorphone HCl Injection, USP CII 1 mg/mL PROTECT FROM LIGHT Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 1 mg/mL Ampule Label
PRINCIPAL DISPLAY PANEL - 1 mg/mL Ampule Box 1 mL 10 Single-use ampuls NDC 0409-2552-01 Rx only HYDROmorphone HCl Injection, USP 1 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. Do not use if solution is discolored or contains a precipitate. Usual Dosage: See insert. Hospira PRINCIPAL DISPLAY PANEL - 1 mg/mL Ampule Box
PRINCIPAL DISPLAY PANEL - 2 mg/mL Ampule Label RL - 4973 Rx only NDC 0409-3356-11 1 mL Single-use ampul HYDROmorphone HCl Injection, USP CII 2 mg/mL PROTECT FROM LIGHT Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 2 mg/mL Ampule Label
PRINCIPAL DISPLAY PANEL - 2 mg/mL Ampule Box 1 mL 10 Single-use ampuls NDC 0409-3356-01 Rx only HYDROmorphone HCl Injection, USP 2 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. Do not use if solution is discolored or contains a precipitate. Usual Dosage: See insert. Hospira PRINCIPAL DISPLAY PANEL - 2 mg/mL Ampule Box
PRINCIPAL DISPLAY PANEL - 4 mg/mL Ampule Label RL - 4949 NDC 0409-2540-11 Rx only 1 mL Single-use ampul HYDROmorphone HCl Injection, USP CII 4 mg/mL PROTECT FROM LIGHT Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 4 mg/mL Ampule Label
PRINCIPAL DISPLAY PANEL - 4 mg/mL Ampule Box 1 mL 10 Single-use ampuls NDC 0409-2540-01 Rx only HYDROmorphone HCl Injection, USP 4 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. Do not use if solution is discolored or contains a precipitate. Usual Dosage: See insert. Hospira PRINCIPAL DISPLAY PANEL - 4 mg/mL Ampule Box
PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Label 1mL Single-dose vial Rx only NDC 0409-3365-11 HYDROmorphone HCl Injection, USP 2 mg/mL CII PROTECT FROM LIGHT Dist. by Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Label
PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Tray 1 mL 25 Single-dose vials Rx only NDC 0409-3365-01 Contains 25 of NDC 0409-3365-11 HYDROmorphone HCl Injection, USP 2 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira PRINCIPAL DISPLAY PANEL - 2 mg/mL Vial Tray
PRINCIPAL DISPLAY PANEL - 1 mg/mL Cartridge Label 1 mL Single-dose Carpuject™ Sterile Cartridge Unit with Luer Lock NDC 0409-1283-03 Rx only HYDROmorphone HCl Injection, USP 1 mg/mL CII PAA198794 PROTECT FROM LIGHT Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira #####AA DMMMYYYY PRINCIPAL DISPLAY PANEL - 1 mg/mL Cartridge Label
PRINCIPAL DISPLAY PANEL - 1 mg/mL Cartridge Carton NDC 0409-1283-31 Contains 10 of NDC 0409-1283-03 Rx only 1 mL Single-dose 10 Carpuject™ Sterile Cartridge Units with Luer Lock Needle not included SLIM-PACK™ Tamper Detection Package HYDROmorphone HCl Injection, USP 1 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Carpuject Cartridges are to be used ONLY with Carpuject Holders. Hospira PRINCIPAL DISPLAY PANEL - 1 mg/mL Cartridge Carton
PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Label 1 mL Single-dose NDC 0409-1283-09 Rx only HYDROmorphone HCl Injection, USP 1 mg/mL CII PROTECT FROM LIGHT PAA128342 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Label
PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Label - PAA128343 NDC 0409-1283-09 Rx only iSecure™ SYRINGE 1 mL Single-dose Syringe with Luer Lock HYDROmorphone HCl Injection, USP 1 mg/mL CII PROTECT FROM LIGHT Dist. by Hospira, Inc. Lake Forest, IL 60045 USA Hospira PAA128343 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Label - PAA128343
PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Carton 10 x 1 mL Single-dose Prefilled Syringe with Luer Lock NDC 0409-1283-10 Contains 10 of NDC 0409-1283-09 Rx only iSecure™ SYRINGE HYDROmorphone HCl Injection, USP 1 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Hospira PRINCIPAL DISPLAY PANEL - 1 mg/mL Syringe Carton
PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Label 0.5 mL Single-dose NDC 0409-1283-04 Rx only HYDROmorphone HCl Injection, USP 0.5 mg/0.5 mL CII PROTECT FROM LIGHT PAA128029 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Label
PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Label - PAA128030 NDC 0409-1283-04 Rx only iSecure™ SYRINGE 0.5 mL Single-dose Syringe with Luer Lock HYDROmorphone HCl Injection, USP 0.5 mg/0.5 mL PROTECT FROM LIGHT Dist. by Hospira, Inc. Lake Forest, IL 60045 USA Hospira PAA128030 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Label - PAA128030
PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Carton 10 x 0.5 mL Single-use Prefilled Syringe with Luer Lock NDC 0409-1283-05 Rx only iSecure™ SYRINGE HYDROmorphone HCl Injection, USP CII 0.5 mg/0.5 mL Hospira For Intravenous, Intramuscular, or Subcutaneous Use PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Carton
PRINCIPAL DISPLAY PANEL - 2 mg/mL Cartridge Label 1 mL Single-dose Carpuject™ Sterile Cartridge Unit with Luer Lock NDC 0409-1312-03 Rx only HYDROmorphone HCl Injection, USP 2 mg/mL CII PROTECT FROM LIGHT Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira PAA198795 #####AA DMMMYYYY PRINCIPAL DISPLAY PANEL - 2 mg/mL Cartridge Label
PRINCIPAL DISPLAY PANEL - 2 mg/mL Cartridge Carton NDC 0409-1312-30 Contains 10 of NDC 0409-1312-03 Rx only 1 mL Single-dose 10 Carpuject™ Sterile Cartridge Units with Luer Lock Needle not included SLIM-PAK™ Tamper Detection Package HYDROmorphone HCl Injection, USP 2 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Carpuject Cartridges are to be used ONLY with Carpuject Holders. Hospira PRINCIPAL DISPLAY PANEL - 2 mg/mL Cartridge Carton
PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Label 1 mL Single-dose NDC 0409-1312-09 Rx only HYDROmorphone HCl Injection, USP 2 mg/mL CII PROTECT FROM LIGHT PAA128349 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Label
PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Label - PAA128350 NDC 0409-1312-09 Rx only iSecure™ SYRINGE 1 mL Single-dose Syringe with Luer Lock HYDROmorphone HCl Injection, USP 2 mg/mL CII PROTECT FROM LIGHT Dist. by Hospira, Inc. Lake Forest, IL 60045 USA Hospira PAA128350 LOT #####AA EXP DMMMYYYY PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Label - PAA128350
PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Carton 10 x 1 mL Single-dose Prefilled Syringe with Luer Lock NDC 0409-1312-10 Contains 10 of NDC 0409-1312-09 Rx only iSecure™ SYRINGE HYDROmorphone HCl Injection, USP 2 mg/mL CII Hospira For Intravenous, Intramuscular, or Subcutaneous Use PRINCIPAL DISPLAY PANEL - 2 mg/mL Syringe Carton
PRINCIPAL DISPLAY PANEL - 4 mg/mL Cartridge Label 1 mL Single-dose Carpuject™ Sterile Cartridge Unit with Luer Lock NDC 0409-1304-03 Rx only HYDROmorphone HCl Injection, USP 4 mg/mL CII PROTECT FROM LIGHT Distributed by Hospira, Inc., Lake Forest, IL 60045 USA Hospira PAA198796 #####AA DMMMYYYY PRINCIPAL DISPLAY PANEL - 4 mg/mL Cartridge Label
PRINCIPAL DISPLAY PANEL - 4 mg/mL Cartridge Carton NDC 0409-1304-31 Contains 10 of NDC 0409-1304-03 Rx only 1 mL Single-dose 10 Carpuject™ Sterile Cartridge Units with Luer Lock Needle not included SLIM-PAK™ Tamper Detection Package HYDROmorphone HCl Injection, USP 4 mg/mL CII For Intravenous, Intramuscular, or Subcutaneous Use Carpuject Cartridges are to be used ONLY with Carpuject Holders. Hospira PRINCIPAL DISPLAY PANEL - 4 mg/mL Cartridge Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Boxed Warning 12/2023 Indications and Usage ( 1 ) 12/2023 Dosage and Administration ( 2.1 , 2.2 , 2.5 ) 12/2023 Warnings and Precautions ( 5.5 ) 12/2023
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.LAB-1381-2.0 Revised: 12/2023
HYDROMORPHONE HYDROCHLORIDE: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Addiction, Abuse, and Misuse Inform patients that the use of Hydromorphone Hydrochloride Injection, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ] . Instruct patients not to share Hydromorphone Hydrochloride Injection with others and to take steps to protect Hydromorphone Hydrochloride Injection from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydromorphone Hydrochloride Injection or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.2) ] . Hyperalgesia and Allodynia Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.5) , Adverse Reactions (6) ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications. [see Drug Interactions 7 ] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) ] . For Medical Information about Hydromorphone Hydrochoride, please visit www.pfizermedinfo.com or call 1‑800-438-1985. Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-0856-5.0 Logo
Instructions for use
Information about safe handling and use of the drug product.INSTRUCTIONS FOR USE Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if color is darker than pale yellow, if it is discolored in any other way, or if it contains a precipitate. Instructions for use - Carpuject™ Single-dose Cartridge Carpuject™ Single-dose cartridges with Luer Lock are packaged in a Slim-Pak™ tamper detection package. Note that a needle is not included. Before use, read all instructions for using the Carpuject™ Syringe, which are contained in the product insert for the reusable Carpuject™ Holder. Carpuject™ Single-dose cartridges are to be used ONLY with Carpuject™ Holders. NOTE: To prevent needlestick injuries, do not recap, purposely bend, or break by hand used needles. Do not recap, purposely bend, or break by hand blunt Cannulas. Instructions for use - iSecure™ Single-dose Syringe 1. Remove green tamper evident band in a clockwise motion. 1. Depress (Push) the plunger rod. This will loosen the plunger rod that is located on the outside of the syringe barrel so that the plunger rod can be removed. This will also engage the syringe. Remove the plunger rod. Insert the plunger rod into the back end of the syringe barrel and turn clockwise 2 to 3 times to attach. BEFORE REMOVING LUER TIP CAP, hold the syringe with tip cap upright. Press syringe plunger until plunger moves slightly. This motion breaks the seal between plunger and syringe barrel. 1. Twist the luer tip cap clockwise or counterclockwise to break the tamper evident label. Remove the luer tip cap and discard it. Expel the air by pushing on the plunger rod. Attach needle or blunt cannula if required. image image image image image image image
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Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6) ] . Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and effectiveness of Hydromorphone Hydrochloride Injection in pediatric patients has not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)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 published animal reproduction 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 antagonist, such as naloxone, 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 No effects on teratogenicity or embryotoxicity were observed in pregnant rats given oral doses up to 7 mg/kg/day which is 3-fold higher than the human dose of 24 mg Hydromorphone Hydrochloride Injection (4 mg every 4 hours), on a body surface area basis. In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the human daily dose of 24 mg/day). In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS • Pregnancy: May cause fetal harm. ( 8.1 ) • Geriatric Patients: Use caution during dose selection, starting at the low end of the dosing range while carefully monitoring for side effects. ( 8.5 ) 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 published animal reproduction 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 antagonist, such as naloxone, 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 No effects on teratogenicity or embryotoxicity were observed in pregnant rats given oral doses up to 7 mg/kg/day which is 3-fold higher than the human dose of 24 mg Hydromorphone Hydrochloride Injection (4 mg every 4 hours), on a body surface area basis. In a published study, neural tube defects (exencephaly and cranioschisis) were noted following subcutaneous administration of hydromorphone hydrochloride (19 to 258 mg/kg) on Gestation Day 8 to pregnant hamsters (6.4 to 87.2 times the HDD of 24 mg/day based on body surface area). The findings cannot be clearly attributed to maternal toxicity. No neural tube defects were noted at 14 mg/kg (4.7 times the human daily dose of 24 mg/day). In a published study, CF-1 mice were treated subcutaneously with continuous infusion of 7.5, 15, or 30 mg/kg/day hydromorphone hydrochloride (1.5, 3, or 6.1 times the human daily dose of 24 mg based on body surface area) via implanted osmotic pumps during organogenesis (Gestation Days 7 to 10). Soft tissue malformations (cryptorchidism, cleft palate, malformed ventricles and retina), and skeletal variations (split supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites) were observed at doses 3 times the human dose of 24 mg/day based on body surface area. The findings cannot be clearly attributed to maternal toxicity. 8.2 Lactation Risk Summary Low levels of opioid analgesics have been detected in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Hydromorphone Hydrochloride Injection and any potential adverse effects on the breastfed infant from Hydromorphone Hydrochloride Injection or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Hydromorphone Hydrochloride Injection through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of hydromorphoneis stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. 8.4 Pediatric Use The safety and effectiveness of Hydromorphone Hydrochloride Injection in pediatric patients has not been established. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to hydromorphone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydromorphone Hydrochloride Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.6) ] . Hydromorphone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Hepatic Impairment The pharmacokinetics of hydromorphone are affected by hepatic impairment. Due to increased exposure of hydromorphone, patients with moderate hepatic impairment should be started at one fourth to one half the recommended starting dose depending on the degree of hepatic dysfunction and closely monitored during dose titration. The pharmacokinetics of hydromorphone in patients with severe hepatic impairment has not been studied. A further increase in Cmax and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment The pharmacokinetics of hydromorphone are affected by renal impairment. In addition, in patients with severe renal impairment, hydromorphone appeared to be more slowly eliminated with a longer terminal elimination half-life. Start patients with renal impairment on one-fourth to one-half the usual starting dose depending on the degree of impairment. Patients with renal impairment should be closely monitored during dose titration. [see Clinical Pharmacology (12.3) ]
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 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. How Supplied Hydromorphone Hydrochloride is as a sterile solution in single-dose amplules ,single-dose Carpuject TM cartridges with Luer Lock for use with Carpuject TM Syringe System and Carpuject Holder ONLY, single‑dose iSecureTM prefilled syringes with Luer Lock, and single-dose vials for intravenous, intramuscular, and subcutaneous administration, and available as follows: Unit of Sale Concentration (per total volume) NDC 0409-2552-01 Carton of 10 1 mL fill in 1 mL Single-dose Ampul 1 mg/mL NDC 0409-3356-01 Carton of 10 1 mL fill in 1 mL Single-dose Ampul 2 mg/mL NDC 0409-2540-01 Carton of 10 1 mL fill in 1 mL Single-dose Ampul 4 mg/mL NDC 0409-3365-01 Tray of 25 1 mL fill in 2 mL Single-dose Vial 2 mg/mL NDC 0409-3365-10 Carton of 10 1 mL fill in 2 mL Single-dose Vial 2 mg/mL NDC 0409-1283-31 Carton of 10 1 mL fill in 2.5 mL Carpuject™ Single-dose cartridge with Luer Lock for the use with Carpuject™ Syringe System 1 mg/mL NDC 0409-1312-30 Carton of 10 1 mL fill in 2.5 mL Carpuject™ Single-dose cartridge with Luer Lock for the use with Carpuject™ Syringe System 2 mg/mL NDC 0409-1304-31 Carton of 10 1 mL fill in 2.5 mL Carpuject™ Single-dose cartridge with Luer Lock for the use with Carpuject™ Syringe System 4 mg/mL NDC 0409-1283-05 Carton of 10 0.5 mL fill in 1.5 mL iSecure™ Single-dose Prefilled Syringe with Luer Lock 0.5 mg/0.5 mL NDC 0409-1283-10 Carton of 10 1 mL fill in 1.5 mL iSecure™ Single-dose Prefilled Syringe with Luer Lock 1 mg/mL NDC 0409-1312-10 Carton of 10 1 mL fill in 1.5 mL iSecure™ Single-dose Prefilled Syringe with Luer Lock 2 mg/mL Carpuject™ Single-dose cartridges with Luer Lock are packaged in a Slim-Pak™ tamper detection package. 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° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
Storage and handling
Information about safe storage and handling of the drug product.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.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE INJECTION WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF HYDROMORPHONE HYDROCHLORIDE INJECTION See full prescribing information for complete boxed warning . • Hydromorphone Hydrochloride Injection exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) • Serious, life-threatening, or fatal respiratory depression may occur with use of Hydromorphone Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential. ( 5.2 ) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.3 , 7 ) • If opioid use is required for extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Addiction, Abuse, and Misuse Because the use of Hydromorphone Hydrochloride Injection exposes patients and other users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Hydromorphone Hydrochloride Injection, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Hydromorphone Hydrochloride Injection are essential [see Warnings and Precautions (5.2) ] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Hydromorphone Hydrochloride Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) , Drug Interactions (7) ] . Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for a prolonged extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4) ] .
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API