Dilaudid-HP Injection, Dilaudid-HP Lyophilized Powder 250 mg (Abbott)

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WARNING:   
DILAUDlD-HP ^® (HIGH POTENCY) IS A HIGHLY CONCENTRATED SOLUTION OF HYDROMORPHONE INTENDED FOR USE IN OPIOID-TOLERANT PATIENTS. DO NOT CONFUSE DILAUDID-HP WITH STANDARD PARENTERAL FORMULATIONS OF DILAUDID OR OTHER OPIOIDS. OVERDOSE AND DEATH COULD RESULT.

DESCRIPTION

DILAUDID (hydromorphone hydrochloride), a hydrogenated ketone of morphine, is an opioid analgesic. HIGH POTENCY DILAUDID is available in AMBER ampules or single dose vials for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each 1 mL of sterile solution contains 10 mg hydromorphone hydrochloride with 0.2% sodium citrate, and 0.2% citric acid solution.

It is also available as lyophilized DILAUDID for intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. Each single dose vial contains 250 mg sterile, lyophilized hydromorphone HCl to be reconstituted with 25 mL of Sterile Water for Injection USP to provide a solution containing 10 mg/mL.

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

M.W. 321.8

CLINICAL PHARMACOLOGY

Many of the effects described below are common to the class of opioid analgesics. In some instances, data may not exist to demonstrate that DILAUDID-HP possesses similar or different effects than those observed with other opioid analgesics. However, in the absence of data to the contrary, it is assumed that DILAUDID-HP would possess these effects.

Central Nervous System:    Opioid analgesics have multiple actions but 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 occurs without loss of consciousness. Opioid analgesics also suppress the cough reflex and 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. Opioid 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 produce respiratory depression by 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 when asphyxia intervenes.

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 antrum portion of the stomach 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 and/or peripheral vasodilation may include pruritis, flushing, and red eyes.

Effects on the myocardium after intravenous administration of opioids are not significant in normal persons, vary with different opioid analgesic agents and vary with the hemodynamic state of the patient, state of hydration and sympathetic drive.

PHARMACOKINETICS

In normal human volunteers hydromorphone hydrochloride is metabolized primarily in the liver. It is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites.

Following intravenous administration of DILAUDID to normal volunteers, the mean half-life of elimination was 2.64 ± 0.88 hours. The mean volume of distribution was 91.5 liters, suggesting extensive tissue uptake. Hydromorphone hydrochloride is rapidly removed from the blood stream and distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. Hydromorphone hydrochloride also crosses the placental membranes.

In terms of area under the analgesic time-effect curve, hydromorphone hydrochloride is approximately 8 times more potent than morphine (i.e., 1.3 mg of hydromorphone hydrochloride produces analgesia equal to that produced by 10 mg of morphine). After intramuscular administration, hydromorphone hydrochloride has a slightly more rapid onset and slightly shorter duration of action than morphine. The duration of DILAUDID analgesia in the non-tolerant patient with usual doses may be up to 4-5 hours. However, in tolerant subjects, duration will vary substantially depending on tolerance and dose. Dose should be adjusted so that 3-4 hours of pain relief may be achieved.

INDICATIONS AND USAGE

DILAUDID-HP is indicated for the relief of moderate-to-severe pain in opioid-tolerant patients who require larger than usual doses of opioids to provide adequate pain relief. Because DILAUDlD-HP contains 10 mg of hydromorphone hydrochloride per mL, a smaller injection volume can be used than with other parenteral opioid formulations. Discomfort associated with the intramuscular or subcutaneous injection of an unusually large volume of solution can therefore be avoided.

CONTRAINDICATIONS

DILAUDID-HP is contraindicated in: patients who are not already receiving large amounts of parenteral opioids, patients with known hypersensitivity to the drug, patients with respiratory depression in the absence of resuscitative equipment, and in patients with status asthmaticus. DILAUDID-HP is also contraindicated for use in obstetrical analgesia.

WARNINGS - DRUG DEPENDENCE

DILAUDID is a Schedule II narcotic. DILAUDID-HP can produce drug dependence of the morphine type and therefore has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration of DILAUDID-HP, and it should be prescribed and administered with the same degree of caution appropriate for the use of morphine. Since DILAUDID-HP is indicated for use in patients who are already tolerant to and hence physically dependent on opioids, abrupt discontinuance in the administration of DILAUDID-HP is likely to result in a withdrawal syndrome. (see DRUG ABUSE AND DEPENDENCE ).

Neonatal Withdrawal Syndrome:    Infants born to mothers physically dependent on DILAUDID-HP will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. (see DRUG ABUSE AND DEPENDENCE ).

Impaired Respiration:    Respiratory depression is the chief hazard of DILAUDID-HP. 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.

DILAUDID-HP 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 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.

Head Injury and Increased Intracranial Pressure:    The respiratory depressant effects of DILAUDID-HP 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 DILAUDID-HP may produce effects which can obscure the clinical course and neurologic signs of further increase in pressure in patients with head injuries.

Hypotensive Effect:    Opioid analgesics, including DILAUDID-HP, may cause severe hypotension in an individual whose ability to maintain his 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 Interactions ). DILAUDlD-HP may produce orthostatic hypotension in ambulatory patients.

DILAUDlD-HP should be administered with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Sulfites:    Contains sodium metabisulfite, 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

General:    Because of its high concentration, the delivery of precise doses of DILAUDID-HP may be difficult if low doses of hydromorphone are required. Therefore, DILAUDID-HP should be used only if the amount of hydromorphone required can be delivered accurately with this formulation.

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 function; 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; or kyphoscoliosis or following gastrointestinal surgery.

In the case of DILAUDID-HP, however, the patient is presumed to be receiving an opioid to which he or she exhibits tolerance and the initial dose of DILAUDID-HP selected should be estimated based on the relative potency of hydromorphone and the opioid previously used by the patient. (see DOSAGE AND ADMINISTRATION ).

The administration of opioid analgesics including DILAUDID-HP may obscure the diagnosis 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 Biliary Surgery:    Opioid analgesics, including DILAUDID-HP, 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: DILAUDID-HP 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 DILAUDID-HP 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 DILAUDID-HP may enhance the action of neuromuscular blocking agents and produce an increased degree of respiratory depression.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with DILAUDID.

DILAUDID was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro chromosome aberration assay in human lymphocytes, or in the in vivo mouse bone marrow micronucleus test.

Fertility in male or female rats was not affected after daily oral administration at doses up to 7 mg/kg/day (41 mg/m ² ). DILAUDID was dosed from 4 weeks prior to mating in males and 2 weeks prior to mating in females.

PREGNANCY-CATEGORY C:

Human:    There are no well-controlled studies in women. Reports based on marketing experience do not identify any specific teratogenic risks following routine (short-term) clinical use. Although there is no clearly defined risk, such reports do not exclude the possibility of infrequent or subtle damage to the human fetus. DILAUDID-HP should be used in pregnant women only when clearly needed (see Labor and Delivery and DRUG ABUSE AND DEPENDENCE ).

Animal:    Neither embryo-fetal toxicity nor teratogenic effects were observed following administration of DILAUDID at oral doses up to 7 mg/kg/day (41 mg/m ² ) in rats from day 6 to day 17 of gestation and up to 25 mg/kg/day (315 mg/m ² ) in rabbits from day 6 to day 20 of gestation.

Literature reports of hydromorphone hydrochloride administration to pregnant Syrian hamsters show that DILAUDID 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.

Nonteratogenic effects:    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:    DILAUDID-HP is 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 DILAUDID-HP since it, and other drugs in this class, may be excreted in the milk.

Pediatric Use:    Safety and effectiveness have not been established.

Geriatric Use:    Clinical studies of DILAUDID 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 PRECAUTIONS ).

ADVERSE REACTIONS

The adverse effects of DILAUDID-HP are similar to those of other 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 lightheadedness, dizziness, sedation, nausea, vomiting, and sweating. 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:    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.

*Hallucinations, although unusual with pure agonist opioids, have been observed in one patient following both a 6 mg and a 4 mg DILAUDID-HP (hydromorphone hydrochloride) dose. However, the patient was receiving several concomitant medications during the second episode and a causal relationship cannot be established.

Cardiovascular:    Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension and hypertension have been reported.

Respiratory:    Bronchospasm and laryngospasm have been known to occur.

Gastrointestinal:    Dry mouth, constipation, biliary tract spasm, ileus, anorexia, diarrhea, cramps and taste alterations have been reported.

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

Dermatologic:    Pruritis, urticaria, other skin rashes, wheal and flare over the vein with intravenous injection, and diaphoresis have been reported with opioid analgesics.

Other:    In clinical trials, neither local tissue irritation nor induration was observed at the site of subcutaneous injection of DILAUDID-HP; pain at the injection site was rarely observed. However, local irritation and induration have been seen following parenteral injection of other opioid drug products.

DRUG ABUSE AND DEPENDENCE

DILAUDID-HP 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 may also be precipitated in the patient with physical dependence by the administration of a drug with opioid antagonist activity, e.g., naloxone (see 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 large 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 DILAUDID-HP should be guided by the degree of tolerance manifested.

In chronic pain patients in whom opioid analgesics including DILAUDID-HP 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. The latter abstinence syndrome may be characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep or "yen" and mydriasis during the first 24 hours. These symptoms may increase in severity and over the next 72 hours may be accompanied by increasing irritability, anxiety, weakness, twitching and spasms of muscles, kicking movements, severe backache, abdominal and leg pains, abdominal and muscle cramps, hot and cold flashes, insomnia, nausea, anorexia, vomiting, intestinal spasm, diarrhea, coryza and repetitive sneezing, increase in body temperature, blood pressure, respiratory rate and heart rate.

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 5-14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2-6 months characterized by insomnia, irritability, muscular aches, and autonomic instability.

In the treatment of physical dependence on DILAUDID-HP, 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 given 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 DILAUDID-HP 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.

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 DILAUDID-HP for chronic pain.

NOTE: In such an individual who is physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist in such a person should be avoided. If necessary to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual 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 DILAUDID-HP. A dose of naloxone (usually 0.4 to 2.0 mg) 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 DILAUDID-HP. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome.

Since the duration of action of DILAUDID-HP 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

Parenteral:    DILAUDID-HP SHOULD BE GIVEN ONLY TO PATIENTS WHO ARE ALREADY RECEIVING LARGE DOSES OF OPIOIDS. DILAUDID-HP is indicated for relief of moderate-to-severe pain in opioid-tolerant patients. Thus, these patients will already have been treated with other opioid analgesics. If the patient is being changed from regular DILAUDID to DILAUDlD-HP, similar doses should be used, depending on the patient's clinical response to the drug. If DILAUDID-HP is substituted for a different opioid analgesic, the following equivalency table should be used as a guide to determine the appropriate dose of DILAUDID-HP (hydromorphone hydrochloride).

In open clinical trials with DILAUDID-HP in patients with terminal cancer, doses ranged from 1-14 mg subcutaneously or intramuscularly; one patient received 30 mg subcutaneously on two occasions. In these trials, both subcutaneous and intramuscular injections of DILAUDID-HP were well-tolerated, with minimal pain and/or burning at the injection site. Mild erythema was rarely noted after intramuscular injection. There was no induration after either intramuscular or subcutaneous administration of DILAUDID-HP. Subcutaneous injections of DILAUDID-HP were particularly well accepted when administered with a short, 30 gauge needle.

Experience with administration of DILAUDID-HP by the intravenous route is limited. Should intravenous administration be necessary, the injection should be given slowly, over at least 2 to 3 minutes. The intravenous route is usually painless.

A gradual increase in dose may be required if analgesia is inadequate, tolerance occurs, or if pain severity increases. The first sign of tolerance is usually a reduced duration of effect.

NOTE:    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A slight yellowish discoloration may develop in DILAUDID-HP ampules. No loss of potency has been demonstrated. DILAUDID injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions.

500 mg/50 mL Vial: To use this single dose presentation, do not penetrate the stopper with a syringe. Instead, remove both the aluminum flipseal and rubber stopper in a suitable work area such as under a laminar flow hood (or equivalent clean air compounding area). The contents may then be withdrawn for preparation of a single, large volume parenteral solution. Any unused portion should be discarded in an appropriate manner.

CAUTION: The packaging (vial stopper) of this product contains rubber latex which may cause allergic reactions.

Reconstitution of sterile lyophilized DILAUDID-HP 250mg: Reconstitute immediately prior to use with 25 mL of Sterile Water for Injection USP to provide a sterile solution containing 10 mg/mL.

SAFETY AND HANDLING INSTRUCTIONS:

DILAUDID-HP poses 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 DILAUDID-HP that is no longer needed.

Access to abusable drugs such as DILAUDID-HP 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. Implementaiton 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

DILAUDID-HP amber ampules and single dose vials contain 10 mg hydromorphone hydrochloride per mL with 0.2% sodium citrate and 0.2% citric acid solution. No added preservative.

NOTE: DILAUDID-HP ampules are amber in color.

The lyophilized DILAUDID-HP Single Dose Vial contains 250 mg of sterile, lyophilized hydromorphone HCl.

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 CII Narcotic.   DEA Order Form Required.

© Abbott

All rights reserved.

Manufactured by

Hospira, Inc., Lake Forest, IL 60045 USA

For Abbott Laboratories, North Chicago, IL 60064, USA

Revised: March, 2005

Ref. EN-0781

Abbott LABORATORIES

NORTH CHICAGO, IL 60064, U.S.A.

PRINTED IN U.S.A.

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