Hydromorphone Hydrochloride - ETHEX Corporation

Hydromorphone Hydrochloride Tablets, USP CII
2 mg, 4 mg, and 8 mg

R_x Only

P4953-2 12/06

WARNING: HYDROMORPHONE HYDROCHRLORIDE 2 MG, 4 MG, and 8 MG 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, a hydrogenated ketone of morphine, is an opioid analgesic.

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

C₁₇H₁₉NO₃·HClDESCRIPTION

Hydromorphone hydrochloride tablets, for oral administration, contain 2 mg hydromorphone hydrochloride (blue tablet), 4 mg hydromorphone hydrochloride (tan tablet), and 8 mg hydromorphone hydrochloride (white tablet).

Other ingredients include colloidal silicon dioxide, lactose hydrous, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The 2 mg tablet also contains FD&C Blue No. 1 aluminum lake. The 4 mg tablet also contains FD&C Blue No. 1 aluminum lake, FD&C Red No. 40 aluminum lake, and FD&C Yellow No. 6 aluminum lake.

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.

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 of 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 a 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.

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 (30-100 g in adults, 1-2 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 massages 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 (2 mg, 4 mg, 8 mg): 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 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 lower starting dose (See CLINICAL PHARMACOLOGY: 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 2-4 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 3-4 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 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 ½ to ⅔ 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 5-15% 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 healthcare 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 abusable drugs such as hydromorphone hydrochloride tablets presents an occupational hazard for addiction in the healthcare industry. Routine procedures for handling controlled substances developed to protect the public may not be adequate to protect healthcare 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 healthcare providers.

Hydromorphone hydrochloride tablets, USP, for oral administration, are supplied as follows:

2 mg: Round, flat face, beveled-edge blue tablet, debossed “E” on one side and “2” on the other side.
100 Count Bottle…………………………..NDC 58177-620-04
1000 Count Bottle…………………………NDC 58177-620-09
100 Count Unit Dose Packs……………….NDC 58177-620-11

4 mg: Round, flat face, beveled-edge tan tablet, debossed “E” on one side and “4” on the other side.
100 Count Bottles…………………………NDC 58177-621-04
1000 Count Bottles……………………….NDC 58177-621-09
100 Count Unit Dose Packs………………NDC 58177-621-11

8 mg: Round, flat face, beveled-edge white tablet, debossed “E” on one side and “8” through partial bisect on the other side.
100 Count Bottle…………………………..NDC 58177-449-04
1000 Count Bottle…………………………NDC 58177-449-09
100 Count Unit Dose Packs………………NDC 58177-449-11

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

A Schedule CII Narcotic. DEA Order Form Is Required.

Manufactured by
KV Pharmaceutical Co. for
ETHEX Corporation
St. Louis, MO  63044

P4953-1                            10/06