HYDROMORPHONE
HYDROCHLORIDE TABLETS USP
8 mg

HYDROMORPHONE HYDROCHLORIDETABLETS 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, 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 is 4,5α-epoxy-3-hydroxy-17-methylmorphinan-6-one hydrochloride. The structural formula of hydromorphone hydrochloride is:

Each Hydromorphone Hydrochloride Tablet USP, 8 mg contains:

•  Hydromorphone Hydrochloride USP . . . . . . . . . . . . 8 mg

In addition, each tablet contains the following inactive ingredients: lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF and stearic acid NF.

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 (C_max and AUC_0-24) 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%).

After oral administration of hydromorphone hydrochloride tablets, 8 mg, peak plasma hydromorphone concentrations are generally attained within 1/2 to 1-hour.

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.

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.

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.

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 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.

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 (seeWARNINGS 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.

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). 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, mydriasis. Other 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.

Patients receiving hydromorphone hydrochloride tablets or their caregivers should be given the following information by the physician, nurse, or pharmacist:

• Patients should be aware that hydromorphone hydrochloride tablets contain hydromorphone, which is a morphine-like substance and which could cause severe adverse effects including respiratory depression and even death if not taken according to the prescriber's directions.
• Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.
• Patients should be advised not to adjust the dose of hydromorphone hydrochloride tablets without consulting the prescribing professional.
• Patients should be advised that hydromorphone hydrochloride tablets may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).
• Patients should not combine hydromorphone hydrochloride tablets with alcohol or other central nervous system depressants (sleep aids, tranquilizers) except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death.
• Women of childbearing potential who become, or are planning to become pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.
• Patients should be advised that hydromorphone hydrochloride tablets are a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.
• Patients should be advised that if they have been receiving treatment with hydromorphone hydrochloride tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the hydromorphone hydrochloride tablets dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.
• Patients should be instructed to keep hydromorphone hydrochloride tablets in a secure place out of the reach of children. When hydromorphone hydrochloride tablets are no longer needed, the unused tablets should be destroyed by flushing down the toilet.

No carcinogenicity studies have been conducted in animals.

Hydromorphone was not mutagenic in the in vitro Ames reverse mutation assay or the human lymphocyte chromosome aberration assay. Hydromorphone was not clastogenic in the in vivo mouse micronucleus assay.

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 equivalent to the human dose of 2.5 to 10 mg every 3 to 6 hours for oral liquid, and 3-fold higher than the human dose of 2 to 4 mg every 4 to 6 hours for the tablet on a body surface area basis.

The major hazards of hydromorphone hydrochloride tablets include respiratory depression and apnea. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.

The most frequently observed 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.

Serious overdosage with hydromorphone hydrochloride tablets is characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension. In serious overdosage, particularly following intravenous injection, apnea, circulatory collapse, cardiac arrest and death may occur.

In the treatment of overdosage, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal.

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 hydromorphone hydrochloride tablets. 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 hydromorphone hydrochloride tablets. In such cases, an abrupt or complete reversal of narcotic effects may precipitate an acute withdrawal syndrome. Since the duration of action of hydromorphone hydrochloride tablets 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.

The usual starting dose for hydromorphone hydrochloride tablets USP is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of hydromorphone hydrochloride tablets USP, 8 mg must be decided by careful evaluation of each clinical situation.

A gradual increase in dose may be required if analgesia is inadequate, as tolerance develops, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

Patients with hepatic and renal impairment should be started on a lower starting dose (see CLINCIAL PHARMCOLOGY: Pharmacokinetics and Metabolism).

The dosage of opioid analgesics like hydromorphone hydrochloride should be individualized for any given patient, since adverse events can occur at doses that may not provide complete freedom from pain.

Safe and effective administration of opioid analgesics to patients with acute or chronic pain depends upon a comprehensive assessment of the patient. The nature of the pain (severity, frequency, etiology, and pathophysiology) as well as the concurrent medical status of the patient will affect selection of the starting dosage.

In non-opioid-tolerant patients, therapy with hydromorphone is typically initiated at an oral dose of 2 to 4 mg every four hours, but elderly patients may require lower doses (see PRECAUTIONS - Geriatric Use).

In patients receiving opioids, both the dose and duration of analgesia will vary substantially depending on the patient's opioid tolerance. The dose should be selected and adjusted so that at least 3 to 4 hours of pain relief may be achieved. In patients taking opioid analgesics, the starting dose of hydromorphone hydrochloride should be based on prior opioid usage. This should be done by converting the total daily usage of the previous opioid to an equivalent total daily dosage of oral hydromorphone hydrochloride using an equianalgesic table (see below). For opioids not in the table, first estimate the equivalent total daily usage of oral morphine, then use the table to find the equivalent total daily dosage of hydromorphone hydrochloride.

Once the total daily dosage of hydromorphone hydrochloride has been estimated, it should be divided into the desired number of doses. Since there is individual variation in response to different opioid drugs, only ¹/₂ to ²/₃ of the estimated dose of hydromorphone hydrochloride calculated from equivalence tables should be given for the first few doses, then increased as needed according to the patient's response.

Since the pharmacokinetics of hydromorphone are affected in hepatic and renal impairment with a consequent increase in exposure, patients with hepatic and renal impairment should be started on a lower starting dose (see CLINCIAL PHARMCOLOGY: Pharmacokinetics and Metabolism).

In chronic pain, doses should be administered around-the-clock. A supplemental dose of 5 to 15% of the total daily usage may be administered every two hours on an "as-needed" basis.

Periodic reassessment after the initial dosing is always required. If pain management is not satisfactory and in the absence of significant opioid-induced adverse events, the hydromorphone dose may be increased gradually. If excessive opioid side effects are observed early in the dosing interval, the hydromorphone dose should be reduced. If this results in breakthrough pain at the end of the dosing interval, the dosing interval may need to be shortened. Dose titration should be guided more by the need for analgesia than the absolute dose of opioid employed.

Hydromorphone hydrochloride tablets contain hydromorphone, a Schedule II controlled opioid agonist. Schedule II opioid substances which include morphine, oxycodone, oxymorphone, fentanyl, and methadone have the highest potential for abuse and risk of fatal overdose. Hydromorphone can be abused and is subject to criminal diversion.

Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage, but it may occur after as little as a week of opioid use. Physical dependence and tolerance are separate and distinct from abuse and addiction.

Addiction is a chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include 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.

“Drug-seeking” behavior is very common in addicts and drug abusers. 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, forging or counterfeiting 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 drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

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. Since hydromorphone hydrochloride tablets may be diverted for non-medical use, 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, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Hydromorphone hydrochloride tablets are intended for oral use only. Misuse or abuse of hydromorphone hydrochloride tablets pose a risk of overdose and death. This risk is increased with concurrent abuse of alcohol and other CNS depressants. Parenteral drug abuse can potentially result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. In addition, parenteral abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Hydromorphone hydrochloride tablets pose little risk of direct exposure to health care personnel and should be handled and disposed of prudently in accordance with hospital or institutional policy. Significant absorption from dermal exposure is unlikely. Patients and their families should be instructed to flush any hydromorphone hydrochloride tablets that are no longer needed.

Access to abuseable drugs such as hydromorphone hydrochloride tablets 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.

Hydromorphone Hydrochloride Tablets USP, 8 mg are available as a white to off-white arc triangle shaped tablet debossed with a bisected “M” on one side and a split “8” on the other side.

•  Bottles of 100 ………… NDC No. 0406-3249-01

STORAGE: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Protect from light.

A Schedule CII Narcotic. DEA Order Form is required.

Mallinckrodt Inc.
St. Louis, MO 63134 U.S.A.

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Mallinckrodt

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Rev 100906