Hydromorohone

Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is an opioid analgesic.

The chemical name of hydromorphone hydrochloride is morphinan-6-one, 4,5-epoxy-3-hydroxy-17-methyl-, hydrochloride, (5α)-. The structural formula is:

C17H19NO3 · HCl M.W. 321.81

Each Hydromorphone Hydrochloride Tablet USP, for oral administration, contains 8 mg hydromorphone hydrochloride. In addition, the tablets include lactose anhydrous and magnesium stearate.

The analgesic activity of hydromorphone hydrochloride tablets 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 8 mg tablet is approximately 24% (coefficient of variation 21%).

Absorption

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

Food effects

In a study conducted with a single 8 mg dose of hydromorphone hydrochloride (four 2 mg 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.

Special Populations

After oral administration of hydromorphone hydrochloride at a single 4 mg dose (two 2 mg 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).

After oral administration of hydromorphone hydrochloride at a single 4 mg dose (two 2 mg 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).

Pharmacokinetics of hydromorphone have not been evaluated in children.

Age has no effect on the pharmacokinetics of hydromorphone.

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.

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.

Hydromorphone Hydrochloride Tablets USP, 8 mg are contraindicated in: patients with known hypersensitivity to hydromorphone, patients with respiratory depression in the absence of resuscitative equipment, and in patients with status asthmatics. Hydromorphone Hydrochloride Tablets USP, 8 mg are also contraindicated for use in obstetrical analgesia.

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 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.

Tolerance and Physical Dependence

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, and 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.

Information for Patients/Caregivers

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

1. 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.
2. 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.
3. Patients should be advised not to adjust the dose of hydromorphone hydrochloride tablets without consulting the prescribing professional.
4. 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).
5. 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.
6. 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.
7. Patients should be advised that hydromorphone hydrochloride tablets is 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.
8. 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 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.
9. 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.

Drug Interactions

The concomitant use of other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers and alcohol may produce additive depressant effects. Respiratory depression, hypotension and profound sedation or coma may occur. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Hydromorphone hydrochloride tablets should not be taken with alcohol. Opioid analgesics, including hydromorphone hydrochloride tablets may enhance the action of neuromuscular blocking agents and produce an excessive degree of respiratory depression.

Interactions with Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, and buprenorphine) should be administered with caution to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic such as hydromorphone. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of hydromorphone and/or may precipitate withdrawal symptoms in these patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

No effects on teratogenicity or embryotoxicity were observed in female rats given oral doses up to 7 mg/kg/day, which is approximately 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. Hydromorphone produced skull malformations (exencephaly and cranioschisis) in Syrian hamsters given oral doses up to 20 mg/kg during the peak of organogenesis (gestation days 8 to 9). The skull malformations were observed at doses approximately 2-fold higher than the human dose of 2.5 to 10 mg every 3 to 6 hours for oral liquid, and 7-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. There are no adequate and well-controlled studies of hydromorphone hydrochloride tablets in pregnant women.

Hydromorphone crosses the placenta, resulting in fetal exposure. Hydromorphone hydrochloride tablets should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus (see PRECAUTIONS: Labor and Delivery and DRUG ABUSE AND DEPENDENCE).

Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery

Hydromorphone hydrochloride tablets are contraindicated in Labor and Delivery (see CONTRAINDICATIONS).

Nursing Mothers

Low levels of opioid analgesics have been detected in human milk. As a general rule, nursing should not be undertaken while a patient is receiving hydromorphone hydrochloride tablets since it, and other drugs in this class, may be excreted in the milk.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

Clinical studies of hydromorphone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, 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 (see INDIVIDUALIZATION OF DOSAGE and PRECAUTIONS).

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.

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 USP, 8 mg

Off-white colored, round, scored tablets (Identified 54 403)

NDC 0054-4370-25: Bottles of 100 tablets.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Light-headedness, nausea, vomiting, constipation, dizziness, low blood pressure, flushing, itching, red eyes, and headache.
• May also cause drowsiness and affect a person's ability to drive or operate machinery. Has a higher potential to cause sedation than morphine.
• There is a risk of respiratory depression (unusually slow or shallow breathing) when taking hydromorphone. The risk is higher in the elderly, debilitated, or in those with pre-existing breathing problems, even at dosages usually recommended.
• May also cause the pupils of the eye to constrict (pinpoint pupils). Pinpoint pupils are a common sign of overdose but are not a definite sign.
• Avoid alcohol at all times (alcohol can increase side effects and also blood levels of the drug leading to a fatal overdosage).
• Hydromorphone can be habit-forming (addictive), even at regular doses. It has a high abuse potential, and personal legitimate supplies of hydromorphone may be sought out by drug seekers. Babies born to mothers who are physically dependent on hydromorphone will be born physically dependent on hydromorphone themselves.
• Tolerance may develop to hydromorphone's effect. This means that increasing dosages are needed to maintain the same level of pain relief with time.
• Should be used short-term only. When given long term, may cause withdrawal symptoms if abruptly stopped. Taper dosage off slowly under a doctor's supervision.
• Lower dosages of hydromorphone are needed in people with moderate liver or kidney disease.
• May not be suitable for some people including those any type of pre-existing breathing problems, with severe liver or kidney disease, with head injuries, at risk for low blood pressure, prostatic hypertrophy, with psychiatric conditions, drug or alcohol dependency.
• May interact with a number of other drugs including those that also cause sedation or respiratory depression or which are metabolized by similar hepatic enzymes.
• Hydromorphone is classed as a schedule II controlled drug, because of its high potential for abuse and risk of respiratory depression.

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

• Take exactly as directed and never take more than your doctor has directed. Low dosages are used initially to reduce the risk of side effects.
• Hydromorphone may make you sleepy and impair your reaction time. Do not drive or operate machinery if hydromorphone affects you in this way.
• Do not drink alcohol while taking hydromorphone. It can increase the risk of side effects such as sedation and respiratory depression and increase blood levels of hydromorphone to potentially fatal levels.
• Do not crush, chew, or attempt to dissolve slow release forms of hydromorphone. This may result in a potentially fatal overdose.
• Do not take any other medications with hydromorphone, unless they have been prescribed by your doctor. This includes medicines bought over the counter and herbal supplements.
• May cause a rapid lowering of blood pressure when going from a sitting to a standing position. This may make you feel faint and increase your risk of falling. Always stand up slowly.
• Keep well out of reach of children and pets. Even just one accidental dose can be fatal.
• If you have been taking hydromorphone for more than a few days, do not stop it abruptly. Talk to your doctor about tapering off the dosage.