Hydromorphone Tablets, Solution

WARNING: HYDROMORPHONE HYDROCHLORIDE ORAL SOLUTION AND 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 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 Oral Solution and 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 Oral Solution and Hydromorphone Hydrochloride Tablets would possess all the actions of mu-agonist opioids.

Central Nervous System

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 Oral Solution and Hydromorphone Hydrochloride Tablet overdose.

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 or release of histamine, or both. Other manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, and red eyes.

Pharmacokinetics and Metabolism

The analgesic activity of Hydromorphone Hydrochloride Oral Solution and Hydromorphone Hydrochloride Tablets are 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%). Bioequivalence between the Hydromorphone Hydrochloride 8 mg tablet and an equivalent dose of Hydromorphone Hydrochloride Oral Solution has been demonstrated.

After oral administration of 8 mg Hydromorphone Hydrochloride Oral Solution or tablets, peak plasma hydromorphone concentrations are generally attained within ½ to 1-hour.

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.

At therapeutic plasma levels, hydromorphone is approximately 8 to19% 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.

Special Populations

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 solution is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION ).

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 solution is recommended to adjust the dose (see DOSAGE AND ADMINISTRATION).

Pharmacokinetics of hydromorphone has 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.

CLINICAL TRIALS

Analgesic effects of single doses of Hydromorphone Hydrochloride Oral Solution 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 Solution provided significantly more analgesia than placebo. In another trial, 5 mg and 10 mg of Hydromorphone Hydrochloride Oral Solution were compared to 30 mg and 60 mg of morphine sulfate oral solution. The pain relief provided by 5 mg and 10 mg Hydromorphone Hydrochloride Oral Solution was comparable to 30 mg and 60 mg oral morphine sulfate, respectively.

Hydromorphone Hydrochloride Oral Solution and 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 Oral Solution and Hydromorphone Hydrochloride Tablets are also contraindicated for use in obstetrical analgesia.

Special Risk Patients

Hydromorphone Hydrochloride Oral Solution and 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 Oral Solution and 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 Oral Solution and 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 Oral Solution or 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 Oral Solution and 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 Oral Solution or Hydromorphone Hydrochloride Tablets may produce orthostatic hypotension in ambulatory patients.

Use in Biliary Tract Disease

Opioid analgesics, including Hydromorphone Hydrochloride Oral Solution and 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, 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 Oral Solution or 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 Oral Solution and 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 Oral Solution or Hydromorphone Hydrochloride Tablets without consulting the prescribing professional.
4. Patients should be advised that Hydromorphone Hydrochloride Oral Solution or 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 Oral Solution or 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 Oral Solution or 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.
8. Patients should be advised that if they have been receiving treatment with Hydromorphone Hydrochloride Oral Solution or Hydromorphone Hydrochloride Tablets for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Hydromorphone Hydrochloride Oral Solution or 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.
9. Patients should be instructed to keep Hydromorphone Hydrochloride Oral Solution or Hydromorphone Hydrochloride Tablets in a secure place out of the reach of children. When Hydromorphone Hydrochloride Oral Solution or Hydromorphone Hydrochloride Tablets are no longer needed, the unused solution or 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 Oral Solution or Hydromorphone Hydrochloride Tablets should not be taken with alcohol. Opioid analgesics, including Hydromorphone Hydrochloride Oral Solution and Hydromorphone Hydrochloride Tablets, may enhance the action of neuromuscular blocking agents and produce an excessive degree of respiratory depression.

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 to10 mg every 3 to 6 hours for oral solution, 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 solution, 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 solution, 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 Oral Solution or Hydromorphone Hydrochloride Tablets in pregnant women.

Hydromorphone crosses the placenta, resulting in fetal exposure. Hydromorphone Hydrochloride Oral Solution and Hydromorphone Hydrochloride Tablets 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 ).

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 Oral Solution and 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 Oral Solution or 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 Oral Solution or Hydromorphone Hydrochloride Tablets does 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).

Hydromorphone Hydrochloride Oral Solution, USP

The usual adult oral dosage for Hydromorphone Hydrochloride Oral Solution is one-half (2.5 mL) to two teaspoonfuls (10 mL) (2.5 mg to 10 mg) every 3 to 6 hours as directed by the clinical situation.  Oral dosages higher than the usual dosages may be required in some patients.

Hydromorphone Hydrochloride Tablets

The usual starting dose for Hydromorphone Hydrochloride Tablets is 2 mg to 4 mg, orally, every 4 to 6 hours. Appropriate use of Hydromorphone Hydrochloride Tablets 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 CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism).

INDIVIDUALIZATION OF DOSAGE

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 Oral Solution or Hydromorphone Hydrochloride Tablets 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 Oral Solution or Hydromorphone Hydrochloride Tablets 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 Oral Solution or Hydromorphone Hydrochloride Tablets.

Once the total daily dosage of Hydromorphone Hydrochloride Oral Solution or Hydromorphone Hydrochloride Tablets 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 Oral Solution or Hydromorphone Hydrochloride Tablets calculated from equivalence tables should be given for the first few doses, and 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 CLINICAL PHARMACOLOGY - 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 Oral Solution, USP is a clear, sweet, slightly viscous solution.  It is available in:

Bottles of 1 pint (473 mL) – NDC # 42858-304-16

2 mg Hydromorphone Hydrochloride Tablets, USP are light orange, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “2” on the opposite side. They are available in:

Bottles of 100 - NDC # 42858-301-01
Unit Dose Packages of 100 (4x25) - NDC # 42858-301-25

4 mg Hydromorphone Hydrochloride Tablets, USP are light yellow, round, flat-faced tablets, with beveled edges, debossed with a “P” on one side and the number “4” on the opposite side. They are available in:

Bottles of 100 - NDC # 42858-302-01
Unit Dose Packages of 100 (4x25) - NDC # 42858-302-25
Bottles of 500 - NDC # 42858-302-50

8 mg Hydromorphone Hydrochloride Tablets, USP are white, triangular shaped tablets debossed with a “P” and an inverted “P” separated with a bisect on one side of the tablet and debossed with the number “8” on the other side of the tablet. They are available in:

Bottles of 100 - NDC# 42858-303-01

Healthcare professionals can telephone Rhodes Pharmaceuticals at 1-888-827-0616 for information on this product.

Storage

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

A schedule CS-II Narcotic. DEA Order Form is required.

Marketed by: Rhodes Pharmaceuticals L.P., Coventry, RI 02816

Manufactured by: Halo Pharmaceuticals, Inc., Whippany, NJ 07981

Revised: JUL2013

302270-0D