HYDROMORPHONE HYDROCHLORIDE TABLETS, USP 8 mg  CII

HYDROMORPHONE HYDROCHLORIDE  - hydromorphone hydrochloride tablet 
Actavis Totowa LLC

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HYDROMORPHONE HYDROCHLORIDE TABLETS, USP 8 mg  CII

DESCRIPTION

Hydromorphone hydrochloride, a hydrogenated ketone of morphine, is a narcotic analgesic. The structural formula of hydromorphone hydrochloride is:

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M.W. 321.8

Each tablet contains 8 mg of hydromorphone hydrochloride. In addition, the tablets include lactose anhydrous, magnesium stearate, microcrystalline cellulose and silicon dioxide.

CLINICAL PHARMACOLOGY

Many of the effects described below are common to this class of mu-opioid agonist analgesics. In some instances, data may not exist to distinguish the effects of hydromorphone hydrochloride from those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that hydromorphone hydrochloride would possess all the actions of mu-agonist opioids.

Opioid analgesics exert their primary effects on the central nervous system and organs containing smooth muscle. The principal actions of therapeutic value are analgesia and sedation. 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.

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.

Opioids depress the cough reflex by direct effect on the cough center in the medulla.

Opioids depress 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.

Opioids cause 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) and marked mydriasis occurs with asphyxia.

Gastric, biliary and pancreatic secretions are decreased by opioids. Opioids cause 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. Opioids can cause a marked increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Certain opioids produce peripheral vasodilation which may result in orthostatic hypotension. Release of histamine may occur with opioids and may contribute to drug-induced hypotension. Other manifestations of histamine release may include pruritus, flushing, and red eyes.

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

Pharmacokinetics
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. In vivo bioavailability following single-dose administration of the 8 mg tablet is approximately 24% (coefficient of variation 21%). Dose proportionality between hydromorphone hydrochloride, USP 8 mg tablets and other strength hydromorphone hydrochloride tablets (2 and 4 mg) has not been established.

Absorption

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

Mean (%cv)
Dosage Cmax Tmax AUCT1/2
Form(ng)(hrs)(ng*hr/mL)(hrs)
8 mg Tablet5.5   (33%)0.74  (34%)23.7  (28%)2.6  (18%)

Food effects: The effect on the rate and extent of absorption of hydromorphone hydrochloride tablet when given with food has not been studied.

Distribution

At therapeutic plasma levels, hydromorphone is approximately 8 to 19% bound to plasma proteins. After an i.v. 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 i.v. dose is about 2.3 hours.

Special Populations:

Pediatrics: Pharmacokinetics of hydromorphone have not been evaluated in children.

Hepatic and renal impairment: The effects of hepatic and renal disease on the clearance of hydromorphone are unknown but caution should be taken to guard against possible accumulation if hepatic and/or renal functions are seriously impaired.

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.

INDIVIDUALIZATION OF DOSAGE

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 tablets calculated from equivalence tables should be given for the first few doses, then increased as needed according to the patient's response.

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.

OPIOID ANALGESIC EQUIVALENTS WITH APPROXIMATELY EQUIANALGESIC POTENCY*
Nonproprietary IM or SC ORAL
NameDoseDose
Morphine sulfate10 mg40 to 60 mg
Hydromorphone HCl1.3 to 2 mg6.5 to 7.5 mg
(DILAUDID)
Oxymorphone HCl 1 to 1.1 mg6.6 mg
(Numorphan)
Levorphanol tartrate 2 to 2.3 mg4 mg
(Levo-Dromoran)
Meperidine, pethidine HCl75 to 100 mg300 to 400 mg
(Demerol)
Methadone HCl 10 mg10 to 20 mg
(Dolophine)

*Dosages, and ranges of dosages represented, are a compilation of estimated equipotent dosages from published references comparing opioid analgesics in cancer and severe pain.

INDICATIONS AND USAGE

Hydromorphone hydrochloride, USP 8 mg tablets are indicated for the management of pain in patients where an opioid analgesic is appropriate.

CONTRAINDICATIONS

Hydromorphone hydrochloride, USP 8 mg 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, USP 8 mg tablets are also contraindicated for use in obstetrical analgesia.

WARNINGS

Impaired Respiration: Respiratory depression is the chief hazard of hydromorphone hydrochloride. Respiratory depression occurs most frequently in overdose situations, 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 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.

Drug Dependence

Hydromorphone hydrochloride is a Schedule II narcotic. Hydromorphone hydrochloride can produce drug dependence of the morphine type and therefore have the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of hydromorphone hydrochloride, which should be prescribed and administered with the degree of caution appropriate to the use of morphine. Abrupt discontinuance in the administration of hydromorphone hydrochloride in patients who are physically dependent on opioids is likely to result in a withdrawal syndrome (see DRUG ABUSE AND DEPENDENCE).

Sulfites

Contains sodium bisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

PRECAUTIONS

Special Risk Patients

In general, opioids 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 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.

Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of hydromorphone hydrochloride 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 may produce effects 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, 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 also PRECAUTIONS-Drug Interaction). Therefore, hydromorphone hydrochloride should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Use in Ambulatory Patients: Hydromorphone hydrochloride 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. The addition of other CNS depressants to hydromorphone hydrochloride therapy may produce additive depressant effects, and hydromorphone hydrochloride should not be taken with alcohol.

Use in Biliary Surgery: Opioid analgesics including hydromorphone hydrochloride 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.

Use in Drug and Alcohol Dependent Patients: Hydromorphone hydrochloride should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of narcotic 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.

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. Opioid analgesics, including hydromorphone hydrochloride, may enhance the action of neuromuscular blocking agents and produce an excessive degree of respiratory depression.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies in animals to evaluate the drug's carcinogenic and mutagenic potential or the effect on fertility, have not been conducted.

Pregnancy

Pregnancy Category C: Literature reports of hydromorphone hydrochloride administration to pregnant Syrian hamsters show that hydromorphone hydrochloride is teratogenic at a dose of 20 mg/kg which is 600 times the human dose. A maximal teratogenic effect (50% of fetuses affected) in the Syrian hamster was observed at a dose of 125 mg/kg (738 mg/m2). There are no well-controlled studies in women. Hydromorphone is known to cross placental membranes. Hydromorphone hydrochloride should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus (see Labor and Delivery and DRUG ABUSE AND DEPENDENCE).

Labor and Delivery

Hydromorphone hydrochloride 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 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 Dosages and PRECAUTIONS).

ADVERSE REACTIONS

The adverse effects of hydromorphone hydrochloride are similar to those of other agonist opioid analgesics, and represent established pharmacological effects of the drug class. The major hazards 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. Syncopal reactions and related symptoms in ambulatory patients may be alleviated if the patient lies down.

Less Frequently Observed with Opioid Analgesics

General and CNS

Weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of mood (nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity, paresthesia, muscle tremor, blurred vision, nystagmus, diplopia and miosis, transient hallucinations and disorientation, visual disturbances, insomnia and increased intracranial pressure may occur.

Cardiovascular: Chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension and hypertension have been reported.

Respiratory: Bronchospasm and laryngospasm have been known to occur.

Gastrointestinal: Constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps and taste alteration have been reported.

Genitourinary: Urinary retention or hesitancy, and antidiuretic effects have been reported.

Dermatologic: Urticaria, other skin rashes, and diaphoresis.

DRUG ABUSE AND DEPENDENCE

Hydromorphone hydrochloride is a Schedule II narcotic, similar to morphine. Opioid analgesics may cause psychological and physical dependence (see WARNINGS). Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal symptoms also may be precipitated in the patient with physical dependence by the administration of a drug with opioid antagonist activity, e.g., naloxone (see also OVERDOSAGE).

Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage, but it may become clinically detectable after as little as a week. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. In chronic pain patients, and in opioid-tolerant cancer patients, the dose of hydromorphone hydrochloride should be guided by the degree of tolerance manifested.

In chronic pain patients in whom opioid analgesics including hydromorphone hydrochloride are abruptly discontinued, a severe abstinence syndrome should be anticipated. This may be similar to the abstinence syndrome noted in patients who withdraw from heroin. Because of excessive loss of fluids through sweating, or vomiting and diarrhea, patients experiencing the syndrome usually exhibit marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse can occur. Without treatment most observable symptoms disappear in 5 to 14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, muscular aches, and autonomic instability.

In the treatment of physical dependence on hydromorphone hydrochloride, the patient may be detoxified by gradual reduction of the dosage, although this is unlikely to be necessary in the terminal cancer patient. If abstinence symptoms become severe, the patient may be detoxified with methadone. Temporary administration of tranquilizers and sedatives may aid in reducing patient anxiety. Gastrointestinal disturbances or dehydration should be treated accordingly.

OVERDOSAGE

Serious overdosage with hydromorphone hydrochloride 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.

Opioid-tolerant patient

Since tolerance to the respiratory and CNS depressant effects of opioids develops concomitantly with tolerance to their analgesic effects, serious respiratory depression due to an acute overdose is unlikely to be seen in opioid-tolerant patients receiving the usual therapeutic dosage of hydromorphone hydrochloride for chronic pain.

Note: In such an individual who is physically dependent on opioids, administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome. The severity will depend on the degree of physical dependence and the dose of the antagonist administered. If necessary to treat serious respiratory depression in the physically-dependent patient, the opioid antagonist should be administered with care and by titration, using fractional (one fifth to one tenth) doses of the antagonist.

Non-tolerant patient

The opioid antagonist, naloxone, is a specific antidote against respiratory depression which may result from overdosage, or unusual sensitivity to hydromorphone hydrochloride. A dose of naloxone (usually given as a test dose of 0.4 mg, followed by up to 2 mg if needed) should be administered intravenously, if possible, simultaneously with respiratory resuscitation. The dose can be repeated in 3 minutes. 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 (see Opioid-tolerant patient).

Since the duration of action of hydromorphone hydrochloride 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.

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.

DOSAGE AND ADMINISTRATION

The usual starting dose for hydromorphone hydrochloride tablets is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of the hydromorphone hydrochloride, USP 8 mg tablet 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.

SAFETY AND HANDLING INSTRUCTIONS

Hydromorphone hydrochloride, USP 8 mg 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. Patients and their families should be instructed to flush any hydromorphone hydrochloride, USP 8 mg tablets that are no longer needed.

Access to abusable drugs such as hydromorphone hydrochloride, USP 8 mg 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.

HOW SUPPLIED

Hydromorphone hydrochloride, USP 8 mg tablets are supplied as: white, triangular tablets with convex surface, debossed “A260” on bisected side. Available in bottles of 100s and 500s.

Store at 20 to 25°C (68 to 77°F). [see USP Controlled Room Temperature]

Protect from light.

Dispense in a tight, light resistant container as defined in the USP.

Do not take this product if the safety seal under the cap is broken or missing.

A schedule CII Narcotic. DEA Order Form is Required.

MANUFACTURED BY

Actavis Totowa LLC

990 Riverview Drive

Totowa, NJ 07512 USA

12/06

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

d6f6799c-figure-02

HYDROMORPHONE HYDROCHLORIDE 
hydromorphone hydrochloride   tablet
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)52152-260
Route of AdministrationORALDEA ScheduleCII    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
HYDROMORPHONE HYDROCHLORIDE (HYDROMORPHONE) HYDROMORPHONE HYDROCHLORIDE8 mg
Inactive Ingredients
Ingredient NameStrength
LACTOSE MONOHYDRATE 
MAGNESIUM STEARATE 
CELLULOSE, MICROCRYSTALLINE 
SILICON DIOXIDE 
Product Characteristics
ColorWHITEScore no score
ShapeTRIANGLE (convex surface) Size4mm
FlavorImprint Code A260
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
152152-260-02100 TABLET In 1 BOTTLENone
252152-260-04500 TABLET In 1 BOTTLENone

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA01767209/01/200608/20/2008

Labeler - Actavis Totowa LLC (113844612)
Registrant - Actavis Totowa LLC (113844612)
Establishment
NameAddressID/FEIOperations
Actavis Totowa LLC113844612MANUFACTURE
Revised: 12/2006Actavis Totowa LLC