Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic. Hydromorphone hydrochloride tablets USP are indicated for the management of pain in patients where an opioid analgesic is appropriate.
HYDROMORPHONE HYDROCHLORIDE — hydromorphone hydrochloride tablet
STAT RX USA LLC
HYDROCHLORIDE TABLETS USP
2mg, 4mg, and 8 mg
HYDROMORPHONE HYDROCHLORIDE TABLETS CONTAIN HYDROMORPHONE, WHICH IS A POTENT SCHEDULE II CONTROLLED OPIOID AGONIST. SCHEDULE II OPIOID AGONISTS, INCLUDING MORPHINE, OXYMORPHONE, OXYCODONE, FENTANYL, AND METHADONE, HAVE THE HIGHEST POTENTIAL FOR ABUSE AND RISK OF PRODUCING RESPIRATORY DEPRESSION. ALCOHOL, OTHER OPIOIDS AND CENTRAL NERVOUS SYSTEM DEPRESSANTS (SEDATIVE-HYPNOTICS) POTENTIATE THE RESPIRATORY DEPRESSANT EFFECTS OF HYDROMORPHONE, INCREASING THE RISK OF RESPIRATORY DEPRESSION THAT MIGHT RESULT IN DEATH.
Hydromorphone Hydrochloride Tablets USP, 2 mg, 4 mg, and 8 mg are supplied in tablet form for oral administration.
Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic.
The chemical name of hydromorphone hydrochloride tablets USP is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The structural formula of hydromorphone hydrochloride is:
Each Hydromorphone Hydrochloride Tablet USP, 2 mg contains:
Hydromorphone Hydrochloride USP . . . . . . . . . . . . 2 mg
Each Hydromorphone Hydrochloride Tablet USP, 4 mg contains:
Hydromorphone Hydrochloride USP . . . . . . . . . . . . 4 mg
Each Hydromorphone Hydrochloride Tablet USP, 8 mg contains:
Hydromorphone Hydrochloride USP . . . . . . . . . . . . 8 mg
In addition, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose and stearic acid.
Hydromorphone hydrochloride is a pure opioid agonist with the principal therapeutic activity of analgesia. A significant feature of the analgesia is that it can occur without loss of consciousness. Opioid analgesics also suppress the cough reflex and may cause respiratory depression, mood changes, mental clouding, euphoria, dysphoria, nausea, vomiting and electroencephalographic changes. Many of the effects described below are common to this class of mu-opioid agonist analgesics which includes morphine, oxycodone, hydrocodone, codeine and fentanyl. In some instances, data may not exist to distinguish the effects of hydromorphone hydrochloride tablets from those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that hydromorphone hydrochloride tablets would possess all the actions of mu-agonist opioids.
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 depresses the cough reflex by direct effect on the cough center in the medulla.
Hydromorphone depresses the respiratory reflex by a 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 (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of hydromorphone hydrochloride tablets overdose.
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.
Hydromorphone may produce hypotension as a result of either peripheral vasodilation or release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes.
The analgesic activity of hydromorphone hydrochloride is due to the parent drug, hydromorphone. Hydromorphone is rapidly absorbed from the gastrointestinal tract after oral administration and undergoes extensive first-pass metabolism. Exposure of hydromorphone (Cmax and AUC0-24) is dose-proportional at a dose range of 2 and 8 mg. In vivo bioavailability following single-dose administration of the hydromorphone hydrochloride tablet, 8 mg is approximately 24% (coefficient of variation 21%).
Absorption – After oral administration of hydromorphone hydrochloride tablets, 8 mg, peak plasma hydromorphone concentrations are generally attained within 1/2 to 1-hour.
| Dosage |
| C max |
| T max |
| AUC |
| T 1/2 |
|8 mg Tablet||5.5 (33%)||0.74 (34%)||23.7 (28%)||2.6 (18%)|
Food Effects – In a study conducted with a single 8 mg dose of hydromorphone (2 mg hydromorphone hydrochloride tablets), food lowered Cmax by 25%, prolonged Tmax by 0.8 hour, and increased AUC by 35%. The effects may not be clinically relevant.
Distribution – At therapeutic plasma levels, hydromorphone is approximately 8 to 19% bound to plasma proteins. After an intravenous bolus dose, the steady state of volume 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.
Hepatic Impairment – After oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone hydrochloride tablets), mean exposure to hydromorphone (Cmax 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 a lower dose and closely monitored during dose titration. Pharmacokinetics of hydromorphone in severe hepatic impairment patients has not been studied. Further increase in Cmax and AUC of hydromorphone in this group is expected. As such, starting dose should be even more conservative. Use of oral liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION).
Renal Impairment – After oral administration of hydromorphone at a single 4 mg dose (2 mg hydromorphone hydrochloride tablets), exposure to hydromorphone (Cmax and AUC0-48) is increased in patients with impaired renal function by 2-fold in moderate (CLcr = 40 to 60 mL/min) and 3-fold in 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 longer terminal elimination half-life (40 hr) compared to patients with normal renal function (15 hr). Patients with moderate renal impairment should be started on a lower dose. Starting doses for patients with severe renal impairment should be even lower. Patients with renal impairment should be closely monitored during dose titration. Use of oral liquid is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION).
Pediatrics – Pharmacokinetics of hydromorphone have not been evaluated in children.
Geriatric – Age has no effect on the pharmacokinetics of hydromorphone.
Gender – Gender has little effect on the pharmacokinetics of hydromorphone. Females appear to have higher Cmax (25%) than males with comparable AUC0-24 values. The difference observed in Cmax may not be clinically relevant.
Pregnancy and Nursing Mothers – Hydromorphone crosses the placenta. Hydromorphone is also found in low levels in breast milk, and may cause respiratory compromise in newborns when administered during labor or delivery.
Analgesic effects of single doses of hydromorphone hydrochloride oral liquid administered to patients with post-surgical pain have been studied in double-blind controlled trials. In one study, both 5 mg and 10 mg of hydromorphone hydrochloride oral liquid provided significantly more analgesia than placebo. In another trial, 5 mg and 10 mg of hydromorphone hydrochloride oral liquid were compared to 30 mg and 60 mg of morphine sulfate oral liquid. The pain relief provided by 5 mg and 10 mg hydromorphone hydrochloride oral liquid was comparable to 30 mg and 60 mg oral morphine sulfate, respectively.
Hydromorphone hydrochloride tablets USP are indicated for the management of pain in patients where an opioid analgesic is appropriate.
Hydromorphone hydrochloride tablets are contraindicated in: patients with known hypersensitivity to hydromorphone, patients with respiratory depression in the absence of resuscitative equipment, and in patients with status asthmaticus. Hydromorphone hydrochloride tablets are also contraindicated for use in obstetrical analgesia.
Respiratory Depression – Respiratory depression is the chief hazard of hydromorphone hydrochloride tablets. Respiratory depression is more likely to occur in the elderly, in the debilitated, and in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.
Hydromorphone hydrochloride tablets should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or in patients with preexisting respiratory depression. In such patients even usual therapeutic doses of opioid analgesics may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.
Hydromorphone hydrochloride tablets contain hydromorphone, which is a potent Schedule II controlled opioid agonist. Schedule II opioid agonists, including morphine, oxymorphone, oxycodone, fentanyl, and methadone, have the highest potential for abuse and risk of producing respiratory depression. Alcohol, other opioids and central nervous system depressants (sedative-hypnotics) potentiate the respiratory depressant effects of hydromorphone, increasing the risk of respiratory depression that might result in death.
Hydromorphone is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.
Hydromorphone hydrochloride tablets can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing hydromorphone hydrochloride tablets 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 signs of abuse.
Hydromorphone hydrochloride tablets have been reported as being abused by crushing, chewing, snorting, or injecting the dissolved product. These practices pose a significant risk to the abuser that could result in overdose or death (see WARNINGS and DRUG ABUSE AND DEPENDENCE).
Concerns about abuse, addiction, and diversion should not prevent the proper management of pain.
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.
Hydromorphone may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Neonatal Withdrawal Syndrome – Infants born to mothers physically dependent on hydromorphone hydrochloride tablets will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see DRUG ABUSE AND DEPENDENCE).
Head Injury and Increased Intracranial Pressure – The respiratory depressant effects of hydromorphone hydrochloride tablets with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure. Opioid analgesics including hydromorphone hydrochloride tablets may produce effects on pupillary response and consciousness which can obscure the clinical course and neurologic signs of further increase in intracranial pressure in patients with head injuries.
Hypotensive Effect – Opioid analgesics, including hydromorphone hydrochloride tablets, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs such as phenothiazines or general anesthetics (see PRECAUTIONS, Drug Interactions). Therefore, hydromorphone hydrochloride tablets should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.
Special Risk Patients – Hydromorphone hydrochloride tablets should be given with caution and the initial dose should be reduced in the elderly or debilitated and those with severe impairment of hepatic, pulmonary or renal functions; myxedema or hypothyroidism; adrenocortical insufficiency (e.g., Addison’s Disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; gall bladder disease; acute alcoholism; delirium tremens; kyphoscoliosis or following gastrointestinal surgery.
The administration of opioid analgesics including hydromorphone hydrochloride tablets may obscure the diagnoses or clinical course in patients with acute abdominal conditions and may aggravate preexisting convulsions in patients with convulsive disorders.
Reports of mild to severe seizures and myoclonus have been reported in severely compromised patients, administered high doses of parenteral hydromorphone, for cancer and severe pain. Opioid administration at very high doses is associated with seizures and myoclonus in a variety of diseases where pain control is the primary focus.
Use in Drug and Alcohol Dependent Patients – Hydromorphone hydrochloride tablets should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of opioid tolerance, dependence, and the risk of addiction observed in these patient populations. Abuse of hydromorphone hydrochloride tablets in combination with other CNS depressant drugs can result in serious risk to the patient.
Hydromorphone is an opioid with no approved use in the management of addictive disorders.
Use in Ambulatory Patients – Hydromorphone hydrochloride tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). Patients should be cautioned accordingly. Hydromorphone hydrochloride may produce orthostatic hypotension in ambulatory patients.
Use in Biliary Tract Disease – Opioid analgesics including hydromorphone hydrochloride tablets should also be used with caution in patients about to undergo surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.