Dilaudid (Hydromorphone Hydrochloride) - Clinical Pharmacology

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 DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS from those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that DILAUDID ORAL LIQUID and DILAUDID 8 mg TABLETS would possess all the actions of mu-agonist opioids.

Central Nervous System

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.

Gastrointestinal Tract and Other Smooth Muscle

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.

Cardiovascular System

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 hydrochloride 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 DILAUDID (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%). Bioequivalence between the DILAUDID 8 mg TABLET and an equivalent dose of DILAUDID ORAL LIQUID has been demonstrated. Dose proportionality between DILAUDID 8 mg TABLET and other strength DILAUDID tablets (2 and 4 mg) has not been established.

Absorption

After oral administration of DILAUDID 8 mg liquid or tablets, peak plasma hydromorphone concentrations are generally attained within ½ to 1-hour.

Mean (%cv)
Dosage Form	Cmax (ng)		Tmax (hrs)		AUC (ng*hr/mL)		T½ (hrs)
8 mg Tablet	5.5	(33%)	0.74	(34%)	23.7	(28%)	2.6	(18%)
8 mg Oral Liquid	5.7	(31%)	0.73	(71%)	24.6	(29%)	2.8	(20%)

Food Effects

The effect on the rate and extent of absorption of DILAUDID tablet or oral liquid when given with food has not been studied.

Distribution

At therapeutic plasma levels, hydromorphone is approximately 8-19% 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

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.

CLINICAL TRIALS

Analgesic effects of single doses of DILAUDID ORAL LIQUID administered to patients with post-surgical pain have been studied in double-blind controlled trials. In one study with 61 patients, both 5 mg and 10 mg of DILAUDID ORAL LIQUID provided significantly more analgesia than placebo. In another trial with 80 patients, 5 mg and 10 mg of DILAUDID 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 DILAUDID ORAL LIQUID was comparable to 30 mg and 60 mg oral morphine sulfate, respectively.

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 2-4 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 DILAUDID 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 DILAUDID 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 DILAUDID.

Once the total daily dosage of DILAUDID 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 DILAUDID 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 5-15% 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 (Trade) Name	IM or SC Dose	ORAL Dose
Morphine sulfate	10 mg	40-60 mg
Hydromorphone HCl (DILAUDID)	1.3-2 mg	6.5-7.5 mg
Oxymorphone HCl (Numorphan)	1-1.1 mg	6.6 mg
Levorphanol tartrate (Levo-Dromoran)	2-2.3 mg	4 mg
Meperidine, pethidine HCl (Demerol)	75-100 mg	300-400 mg
Methadone HCl (Dolophine)	10 mg	10-20 mg

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