of excellent [30:80 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 CLINICAL PHARMACOLOGY (12.2) ] . Hepatic 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 hepatic impairment. 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. 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 C max and AUC of hydromorphone in this group is expected and should be taken into consideration when selecting a starting dose [see CLINICAL PHARMACOLOGY (12.2) ] . 9 DRUG ABUSE AND DEPENDENCE Controlled Substance DILAUDID INJECTION and Dilaudid-HP INJECTION contain hydromorphone, which is a Schedule II controlled substance with an abuse liability similar to morphine. DILAUDID can be abused and is subject to criminal diversion. Abuse DILAUDID INJECTION and Dilaudid-HP INJECTION are intended for parenteral use only under the direct supervision of an appropriately licensed health care professional. Abuse of DILAUDID INJECTION and Dilaudid-HP INJECTION poses a hazard of overdose and death. This risk is increased with concurrent abuse of alcohol or other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. DILAUDID INJECTION and Dilaudid-HP INJECTION can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing, dispensing, ordering, or administering DILAUDID INJECTION or Dilaudid-HP INJECTION in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Prescribers should monitor all patients receiving opioids for signs of abuse, misuse, and addiction. Furthermore, patients should be assessed for their potential for opioid abuse prior to being prescribed opioid therapy. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse) or mental illness (e.g., depression). Opioids may still be appropriate for use in these patients, however, they will require intensive monitoring for indications of abuse. Opioid drugs are sought by people with substance use disorders (abuse or addiction, the latter of which is also called substance dependence ) and criminals who supply them by diverting medicines out of legitimate distribution channels. DILAUDID INJECTION and Dilaudid-HP INJECTION are targets for diversion. Drug-seeking behavior is very common in persons with substance use disorders. Drug-seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated loss of prescriptions, altering or forging of prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among people with untreated substance use disorders and criminals who divert controlled substances. The risks of misuse and abuse should be considered when prescribing or dispensing DILAUDID INJECTION or Dilaudid-HP INJECTION. Concerns about abuse and addiction, should not prevent the proper management of pain, however. Treatment of pain should be individualized, balancing the potential benefits and risks for each patient. Addiction is defined as a chronic, neurobiological disorder with genetic, psychosocial, and environmental aspects, characterized by one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, proper dispensing and correct storage and handling are appropriate measures that help to limit misuse and abuse of opioid drugs. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Dependence Tolerance to opioids is demonstrated by the need for increasing doses to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance to different effects of opioids may develop to varying degrees and at varying rates in a given individual. There is also inter-patient variability in the rate and extent of tolerance that develops to various opioid effects, whether the effect is desirable (e.g., analgesia) or undesirable (e.g., nausea). In general, patients taking opioid analgesics that are appropriately titrated for pain control develop tolerance to the respiratory depressant effects fairly reliably. Conversely, tolerance to the constipating effects of opioids rarely develops, even when they are administered over long periods of time. Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, 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. In general, opioids used regularly should not be abruptly discontinued. 10 OVERDOSAGE Signs and Symptoms Signs and symptoms of acute overdosage with DILAUDID INJECTION or Dilaudid-HP INJECTION include: respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, apnea, circulatory collapse, cardiac arrest, and death. Hydromorphone may cause miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis, rather than miosis, may be seen with hypoxia in overdose situations. Treatment In the treatment of overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to DILAUDID INJECTION or Dilaudid-HP INJECTION. Therefore, an appropriate dose of this antagonist should be administered, preferably by the intravenous route, simultaneously with efforts at respiratory resuscitation. Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on DILAUDID INJECTION or Dilaudid-HP INJECTION. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. Since the duration of action of DILAUDID INJECTION and Dilaudid-HP INJECTION may exceed that of the antagonist, the patient should be kept under continued surveillance; repeated doses of the antagonist may be required to maintain adequate respiration. Apply other supportive measures when indicated. 11 DESCRIPTION DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid analgesic. The chemical name of DILAUDID is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The structural formula is: C 17 H 19 NO 3 HCl 321.80 DILAUDID INJECTION is available as a sterile, aqueous solution in COLORLESS ampules for parenteral administration. Each 1 mL ampule contains 1 mg, 2 mg, or 4 mg of hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid added as a buffer to maintain a pH between 3.5 and 5.5. Dilaudid-HP INJECTION is available as a sterile, aqueous solution in AMBER ampules and in AMBER , single-dose vials for intravenous, subcutaneous, or intramuscular administration. Each ampule and single-dose vial contains 10 mg/mL of hydromorphone hydrochloride with 0.2% sodium citrate and 0.2% citric acid added as a buffer to maintain a pH of between 3.5 and 5.5. The single dose vials are capped with stoppers containing natural rubber latex. Dilaudid-HP INJECTION is also available as sterile, lyophilized powder in an AMBER , single-dose vial for reconstitution for intravenous, subcutaneous, or intramuscular administration. Each single dose vial contains 250 mg sterile, lyophilized hydromorphone HCl with either hydrochloric acid or sodium hydroxide added to adjust the pH. Each vial is to be reconstituted with 25 mL of Sterile Water for Injection USP to provide a solution containing 10 mg/mL with a pH between 4.5 and 6.5. The single dose vials are capped with stoppers containing natural rubber latex. 12 CLINICAL PHARMACOLOGY Mechanism of Action The precise mode of analgesic action of opioid analgesics is unknown. However, specific CNS opiate receptors have been identified. Opioids are believed to express their pharmacological effects by combining with these receptors. Hydromorphone hydrochloride is a mu-opioid receptor agonist whose principal therapeutic action is analgesia. Other members of the class known as opioid agonists include substances such as morphine, oxycodone, fentanyl, codeine, hydrocodone, and oxymorphone. Central Nervous System Pharmacological effects of opioid agonists include anxiolysis, euphoria, feelings of relaxation, and cough suppression, as well as analgesia. Hydromorphone produces respiratory depression by direct effect on brain stem respiratory centers. The mechanism of respiratory depression also involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension. Hydromorphone causes miosis. Pinpoint pupils are a common sign of opioid overdose but are not pathognomonic (pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Gastrointestinal Tract and Other Smooth Muscle Gastric, biliary and pancreatic secretions are decreased by opioids such as hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the gastric antrum and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, and tone may be increased to the point of spasm. The end result is constipation. Hydromorphone can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi. Cardiovascular System Hydromorphone may produce hypotension as a result of either peripheral vasodilation, release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes. Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive. Endocrine System Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Immune System In vitro and animal studies indicate that opioids have a variety of effects on immune functions. The clinical significance of these findings is unknown. 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. 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. Elimination 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. 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. Special 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 (8.7) ] . 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]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out 2 CSA Schedule High potential for abuse Approval History Drug history at FDA WADA Class Anti-Doping Classification Drug Class Narcotic analgesics Related Drugs narcotic analgesics tramadol , hydrocodone , oxycodone , morphine , fentanyl , Ultram Chronic Pain tramadol , oxycodone , Cymbalta , duloxetine , Percocet , morphine , fentanyl , More... Pain tramadol , acetaminophen , Tylenol , naproxen , oxycodone , aspirin , ibuprofen , More... Anesthetic Adjunct fentanyl , hydromorphone , butorphanol , Stadol , Sublimaze , methohexital , atracurium , thiopental , More... Dilaudid-HP Rating 8 User Reviews 7.8 /10 8 User Reviews 7.8 Rate it!} } searching for
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