| HYDROMORPH CONTIN® |
|Purdue Frederick |
|Hydromorphone HCl |
|Opioid Analgesic |
|Action And Clinical Pharmacology: Hydromorphone, a semi-synthetic µ opioid agonist, is a hydrogenated ketone of morphine and shares the pharmacologic properties typical of opioid analgesics. Hydromorphone and related opioids produce their major effects on the CNS and gastrointestinal tract. These include analgesia, drowsiness, mental clouding, changes in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure, increased biliary pressure, pinpoint constriction of the pupils, increased parasympathetic activity and transient hyperglycemia.
Estimates of the relative analgesic potency of parenterally administered hydromorphone to morphine in acute pain studies in man range from approximately 7:1 to 11:1.
The relationship between plasma concentration of hydromorphone and analgesic effect has not been well established. In patients with chronic pain, hydromorphone should be titrated to the dose required to adequately relieve pain without unmanageable side effects.
There is no intrinsic limit to the analgesic effect of hydromorphone; like morphine, adequate doses will relieve even the most severe pain. Clinically however, dosage limitations are imposed by the adverse effects, primarily respiratory depression, nausea and vomiting, which can result from high doses.
Pharmacokinetics: After oral administration of conventional release hydromorphone tablets, the drug is rapidly absorbed and, like morphine, undergoes presystemic elimination (approximately 50%), presumably as a result of metabolism in the liver. The terminal elimination half-life after i.v. administration is approximately 2.5 to 3 hours. The pharmacokinetics of hydromorphone have been shown to be linear over a range of i.v. doses from 10 to 40 µg/kg. The principal mode of elimination is by excretion in the urine as hydromorphone-3-glucuronide, which, at steady-state is present in plasma at concentrations approximately 26 times those of the parent drug. The pharmacologic activity of this and other hydromorphone metabolites in humans is not known.
Hydromorphone controlled release capsules administered 12 hourly provides equivalent analgesia to conventional hydromorphone tablets (Dilaudid) administered every 4 hours in patients with cancer pain. Steady-state pharmacokinetic studies demonstrate that maximum plasma concentrations (Cmax) of hydromorphone are achieved at a mean of 4.8 hours after administration of Hydromorph Contin, with maximum and minimum concentrations equivalent to those obtained with 4 hourly administration of the conventional release tablets. The extent of absorption of hydromorphone from Hydromorph Contin is equivalent to that from conventional tablets (Dilaudid) and is not significantly influenced when administered in the presence of food. In patients with chronic cancer pain receiving doses of Hydromorph Contin ranging from 6 mg to 216 mg/day there was a linear relationship between area under the plasma concentration-time curve (AUC) and dose.
Indications And Clinical Uses: For the relief of severe pain requiring the prolonged use of an oral opioid preparation.
Contra-Indications: Should not be given to patients with: hypersensitivity to opioid analgesics; acute asthma or other obstructive airway disease and acute respiratory depression; cor pulmonale; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; suspected surgical abdomen; concomitant MAO inhibitors (or within 14 days of such therapy). tag_WarningWarnings
Manufacturers' Warnings In Clinical States: Drug Dependence: As with other opioids, tolerance and physical dependence tend to develop upon repeated administration of hydromorphone and there is a potential for abuse of the drug and for development of psychological dependence. Hydromorphone should therefore be prescribed and handled with the high degree of caution appropriate to the use of a drug with strong abuse potential. Drug abuse is not a problem in patients with severe pain in which hydromorphone is appropriately indicated. However, in the absence of a clear indication for a strong opioid analgesic, drug-seeking behavior must be suspected and resisted, particularly in individuals with a history of, or propensity for drug abuse. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Therefore, patients on prolonged therapy should be withdrawn gradually from the drug if it is no longer required for pain control.
CNS Depression: Hydromorphone should be used only with caution and in reduced dosage during concomitant administration of other opioid analgesics, general anesthetics, phenothiazines and other tranquilizers, sedative-hypnotics, tricyclic antidepressants and other CNS depressants, including alcohol. Respiratory depression, hypotension and profound sedation or coma may result.
Severe pain antagonizes the subjective and respiratory depressant actions of hydromorphone. Should pain suddenly subside, these effects may rapidly become manifest. Patients who are scheduled for cordotomy or other interruption of pain transmission pathways should not receive hydromorphone within 24 hours of the procedure.
Pregnancy: Animal studies with both morphine and hydromorphone have indicated the possibility of teratogenic effects. While experience in humans has not identified this as a risk, hydromorphone should be given to pregnant patients only when the anticipated benefits outweigh the potential risks to the fetus.
Precautions: General: The respiratory depressant effects of hydromorphone, and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, hydromorphone may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, hydromorphone must be used with extreme caution and only if it is judged essential.
Hydromorphone should be used with extreme caution in patients with substantially decreased respiratory reserve, pre-existing respiratory depression, hypoxia or hypercapnia. Such patients are often less sensitive to the stimulatory effects of carbon monoxide on the respiratory centre and the respiratory depressant effects of hydromorphone may reduce respiratory drive to the point of apnea.
Hydromorphone administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of such drugs as phenothiazines or certain anesthetics.
Hydromorphone may obscure the diagnosis or clinical course of patients with acute abdominal conditions.
Special Risk Groups: Hydromorphone should be administered with caution, and in reduced dosages, to elderly or debilitated patients, to patients with severely reduced hepatic or renal function, and in patients with Addison's disease, hypothyroidism, prostatic hypertrophy or urethral stricture.
Labor/Delivery and Lactation: In view of the potential for opioids to cross the placental barrier and to be excreted in breast milk, hydromorphone should be used with caution during labor or in nursing mothers. Physical dependence or respiratory depression may occur in the infant.
Occupational Hazards: Hydromorphone may impair the mental and/or physical abilities needed for certain potentially hazardous activities such as driving a car or operating machinery. Patients should be cautioned accordingly.
Drug Interactions: CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate and glutethimide may enhance the depressant effects of hydromorphone. MAO inhibitors (including procarbazine HCl), pyrazolidone antihistamines, beta-blockers and alcohol may also enhance the depressant effect of hydromorphone. When combined therapy is contemplated, the dose of one or both agents should be reduced.
Hydromorphone may increase the anticoagulant activity of coumarin and other anticoagulants.
Adverse Reactions: Adverse effects of hydromorphone are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of hydromorphone include respiratory and CNS depression. To a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest have occurred.
The most frequently observed adverse effects are sedation, nausea, vomiting, constipation, lightheadedness, dizziness and sweating.
Sedation: Some degree of sedation is experienced by most patients upon initiation of therapy. This may be at least partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within 3 to 5 days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after 3 or 4 days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension particularly in elderly or debilitated patients and may be alleviated if the patient lies down.
Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting prolonged therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.
Constipation: Practically all patients become constipated while taking opioids on a persisent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid analgesic therapy. Stool softeners, stimulant laxatives and other appropriate measures should be used as required.
Less Frequently Observed with Opioid Analgesics: General and CNS: dysphoria, euphoria, 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; flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension and hypertension.
Respiratory: bronchospasm and laryngospasm.
Gastrointestinal: dry mouth, biliary tract spasm, anorexia, diarrhea, cramps and taste alterations.
Genitourinary: urinary retention or hesitancy and antidiuretic effects.
Dermatologic: pruritus, urticaria, other skin rashes and diaphoresis.
Withdrawal (Abstinence) Syndrome: Physical dependence with or without psychological dependence tend to occur on chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. The following withdrawal symptoms may be observed after opioids are discontinued: body aches, diarrhea, gooseflesh, loss of appetite, nervousness or restlessness, runny nose, sneezing, tremors or shivering, stomach cramps, nausea, trouble with sleeping, unusual increase in sweating and yawning, weakness, tachycardia and unexplained fever. In patients who are appropriately treated with opioid analgesics and who undergo gradual withdrawal from the drug, these symptoms are usually mild.
Symptoms And Treatment Of Overdose: Symptoms: Serious overdosage with hydromorphone may be characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. tag_Treatment
Treatment: Primary attention should be given to the establishment of adequate respiratory exchange through the provision of a patent airway and controlled or assisted ventilation. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression due to overdosage or as a result of unusual sensitivity to hydromorphone. An appropriate dose of the antagonist should therefore be administered, preferably by the i.v. route. The usual initial i.v. adult dose of naloxone is 0.4 mg or higher. Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of hydromorphone, particularly sustained release formulations, may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonist should be repeated as needed to maintain adequate respiration.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Oxygen, i.v. fluids, vasopressors and other supportive measures should be used as indicated.
In individuals physically dependent on opioids, the administration of the usual dose of opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of antagonist administered. The use of opioid antagonists in such individuals should be avoided if possible. If an opioid antagonist must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care by using dosage titration, commencing with 10 to 20% of the usual recommended initial dose.
Evacuation of gastric contents may be useful in removing unabsorbed drug, particularly when a sustained release formulation has been taken.
Dosage And Administration: Adults: Individual dosing requirements vary considerably based on each patient's age, weight, severity and cause of pain, and medical and analgesic history.
Patients currently receiving other oral hydromorphone formulations may be transferred to Hydromorph Contin at the same total daily hydromorphone dosage, equally divided into two 12-hourly Hydromorph Contin doses.
For patients who are receiving an alternate opioid, the "oral hydromorphone equivalent" of the analgesic presently being used should be determined. Having determined the total daily dosage of the present analgesic, Table I can be used to calculate the approximate daily oral hydromorphone dosage that should provide equivalent analgesia. This total daily oral hydromorphone dose should then be equally divided into two 12-hourly Hydromorph Contin doses.
Patients who are opioid naive or receiving low, intermittent doses of weak opioid analgesics may be initiated on Hydromorph Contin 3 mg every 12 hours.
Dose Titration: Dose titration is the key to success with opioid analgesic therapy. Proper optimization of doses scaled to the relief of the individual's pain should aim at the regular administration of the lowest dose which will maintain the patient free of pain at all times. Dosage adjustments should be based on the patient's clinical response.
In patients receiving hydromorphone chronically the dose should be titrated at intervals of 48 hours to that which provides satisfactory pain relief without unmanageable side effects. Hydromorph Contin is designed to allow 12 hourly dosing. If breakthrough pain repeatedly occurs at the end of the dosing interval it is generally an indication for a dosage increase rather than more frequent administration.
Adjustment or Reduction of Dosage: Following successful relief of severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation may become feasible due to a change in the patient's condition or mental state.
Capsules should be swallowed intact. They may be sprinkled on soft food but neither the capsules nor the beads should be crushed or chewed.
Opioid analgesics may only be partially effective in relieving dysesthetic pain, postherpetic neuralgia, stabbing pains, activity-related pain and some forms of headache. That is not to say that patients with advanced cancer suffering from some of these forms of pain should not be given an adequate trial of opioid analgesics, but it may be necessary to refer such patients at an early time to other forms of pain therapy.
Availability And Storage: 3 mg: Each green, controlled release capsule, imprinted with the letters PF and HYDROMORPH CONTIN, and the strength 3 mg, contains: hydromorphone HCl 3 mg. Nonmedicinal ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate and microcrystalline cellulose. Polypropylene bottles of 50.
6 mg: Each pink, controlled release capsule, imprinted with the letters PF and HYDROMORPH CONTIN, and the strength 6 mg, contains: hydromorphone HCl 6 mg. Nonmedicinal ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate and microcrystalline cellulose. Polypropylene bottles of 50.
12 mg: Each orange, controlled release capsule, imprinted with the letters PF and HYDROMORPH CONTIN, and the strength 12 mg, contains: hydromorphone HCl 12 mg. Nonmedicinal ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate and microcrystalline cellulose. Polypropylene bottles of 50.
24 mg: Each grey, controlled release capsule, imprinted with the letters PF and HYDROMORPH CONTIN, and the strength 24 mg, contains: hydromorphone HCl 24 mg. Nonmedicinal ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate and microcrystalline cellulose. Polypropylene bottles of 50.
30 mg: Each red, controlled release capsule, imprinted with the letters PF and HYDROMORPH CONTIN, and the strength 30 mg, contains: hydromorphone HCl 30 mg. Nonmedicinal ingredients: colloidal silicon dioxide, dibutyl sebacate, ethyl cellulose, hydroxypropylmethyl cellulose, magnesium stearate and microcrystalline cellulose.
Store at 15 to 25°C.