Drug: Betapace

Betapace (sotalol hydrochloride) is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a light-blue, capsule-shaped tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3 S·HCl and is represented by the following structural formula: Betapace (sotalol) Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose, starch, stearic acid, magnesium stearate, colloidal silicon dioxide, and FD&C blue color #2 (aluminum lake, conc.).

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During premarketing trials, 3186 patients with cardiac arrhythmias (1363 with sustained ventricular tachycardia) received oral Betapace (sotalol) , of whom 2451 received the drug for at least two weeks. The most important adverse effects are Torsade de Pointes and other serious new ventricular arrhythmias (see WARNINGS), occurring at rates of almost 4% and 1%, respectively, in the VT/VF population. Overall, discontinuation because of unacceptable side-effects was necessary in 17% of all patients in clinical trials, and in 13% of patients treated for at least two weeks. The most common adverse reactions leading to discontinuation of Betapace (sotalol) are as follows: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. Occasional reports of elevated serum liver enzymes have occurred with Betapace (sotalol) therapy but no cause and effect relationship has been established. One case of peripheral neuropathy which resolved on discontinuation of Betapace (sotalol) and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study. Elevated blood glucose levels and increased insulin requirements can occur in diabetic patients. The following table lists as a function of dosage the most common (incidence of 2% or greater) adverse events, regardless of relationship to therapy and the percent of patients discontinued due to the event, as collected from clinical trials involving 1292 patients with sustained VT/VF. Incidence (%) of Adverse Events and Discontinuations
Body System DAILYDOSE 160 mg
(n=832) 240 mg
(n=263) 320 mg
(n=835) 480 mg
(n=459) 640 mg
(n=324) Any Dosea
(n=1292) % Patients Discontinued
(n=1292) Body as a whole infection 1 2 2 2 3 4 < 1 fever 1 2 3 2 2 4 < 1 localized pain 1 1 2 2 2 3 < 1 Cardiovascular dyspnea 5 8 11 15 15 21 2 bradycardia 8 8 9 7 5 16 2 chest pain 4 3 10 10 14 16 < 1 palpitation 3 3 8 9 12 14 < 1 edema 2 2 5 3 5 8 1 ECG abnormal 4 2 4 2 2 7 1 hypotension 3 4 3 2 3 6 2 proarrhythmia < 1 < 1 2 4 5 5 3 syncope 1 1 3 2 5 5 1 heart failure 2 3 2 2 2 5 1 presyncope 1 2 2 4 3 4 < 1 peripheral vascular disorder 1 2 1 1 2 3 < 1 cardiovascular disorder 1 < 1 2 2 2 3 < 1 vasodilation 1 < 1 1 2 1 3 < 1 AICD discharge < 1 2 2 2 2 3 < 1 hypertension < 1 1 1 1 2 2 < 1 Nervous fatigue 5 8 12 12 13 20 2 dizziness 7 6 11 11 14 20 1 asthenia 4 5 7 8 10 13 1 light-headed 4 3 6 6 9 12 1 headache 3 2 4 4 4 8 < 1 sleep problem 1 1 5 5 6 8 < 1 perspiration 1 2 3 4 5 6 < 1 altered consciousness 2 3 1 2 3 4 < 1 depression 1 2 2 2 3 4 < 1 paresthesia 1 1 2 3 2 4 < 1 anxiety 2 2 2 3 2 4 < 1 mood change < 1 < 1 1 3 2 3 < 1 appetite disorder 1 2 2 1 3 3

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As with other antiarrhythmic agents, Betapace (sotalol) should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment (see INDICATIONS AND USAGE). Betapace (sotalol) should be administered only after appropriate clinical assessment (see INDICATIONS AND USAGE), and the dosage of Betapace (sotalol) must be individualized for each patient on the basis of therapeutic response and tolerance. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment. Adults Dosage of Betapace (sotalol) should be adjusted gradually, allowing 3 days between dosing increments in order to attain steady-state plasma concentrations, and to allow monitoring of QT intervals. Graded dose adjustment will help prevent the usage of doses which are higher than necessary to control the arrhythmia. The recommended initial dose is 80 mg twice daily. This dose may be increased, if necessary, after appropriate evaluation to 240 or 320 mg/day (120-160 mg twice daily). In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480640 mg/day; however, these doses should only be prescribed when the potential benefit outweighs the increased risk of adverse events, in particular proarrhythmia. Because of the long terminal elimination half-life of Betapace (sotalol) dosing on more than a BID regimen is usually not necessary. Children As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QTc interval and heart rate. For children aged about 2 years and greater For children aged about 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children (see CLINICAL PHARMACOLOGY) is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m² three times a day (90 mg/m² total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m² (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QTc, with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steadystate plasma concentrations of sotalol in patients with age-adjusted normal renal function. For children aged about 2 years or younger For children aged about 2 years or younger, the above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in months. For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97) = 29.1 mg/m², administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 X 0.68) = 20 mg/m², administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 X 0.3) = 9 mg/m². Similar calculations should be made for increased doses as titration proceeds. Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer. In all children, individualization of dosage is required. As in adults Betapace (sotalol hydrochloride) should be used with particular caution in children if the QTc is greater than 500 msec on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when QTc exceeds 550 msec. Dosage In Renal Impairment Adults Because sotalol is excreted predominantly in urine and its terminal elimination half-life is prolonged in conditions of renal impairment, the dosing interval (time between divided doses) of sotalol should be modified (when creatinine clearance is lower than 60 mL/min) according to the following table. Creatinine Clearance mL/min Dosinga Interval (hours) > 60 12 30-59 24 10-29 36-48 < 10 Dose should be individualized a) The initial dose of 80 mg and subsequent doses should be administered at these intervals. See following paragraph for dosage escalations.   Since the terminal elimination half-life of Betapace (sotalol hydrochloride) is increased in patients with renal impairment, a longer duration of dosing is required to reach steady-state. Dose escalations in renal impairment should be done after administration of at least 5-6 doses at appropriate intervals (see table above). Extreme caution should be exercised in the use of sotalol in patients with renal failure undergoing hemodialysis. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Sotalol, however, can be partly removed by dialysis with subsequent partial rebound in concentrations when dialysis is completed. Both safety (heart rate, QT interval) and efficacy (arrhythmia control) must be closely monitored. Children The use of Betapace (sotalol hydrochloride) in children with renal impairment has not been investigated. Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QTc is more important and it will take much longer to reach steady-state with any dose and/or frequency of administration. Transfer to Betapace (sotalol) Before starting Betapace (sotalol) , previous antiarrhythmic therapy should generally be withdrawn under careful monitoring for a minimum of 2-3 plasma half-lives if the patient's clinical condition permits (see DRUG INTERACTIONS). Treatment has been initiated in some patients receiving I.V. lidocaine without ill effect. After discontinuation of amiodarone, Betapace (sotalol) should not be initiated until the QT interval is normalized (see WARNINGS). Preparation of Extemporaneous Oral Solution BETAPACE (sotalol) Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) available from Humco Laboratories as follows:
  1. Measure 120 mL of Simple Syrup.
  2. Transfer the syrup to a 6-ounce amber plastic (polyethylene terephthalate [PET]) prescription bottle. NOTE: An oversized bottle is used to allow for a headspace, so that there will be more effective mixing during shaking of the bottle.
  3. Add five (5) Betapace (sotalol) 120 mg tablets to the bottle. These tablets are added intact; it is not necessary to crush the tablets. NOTE: The addition of the tablets can also be done first. The tablets can also be crushed if preferred. If the tablets are crushed, care should be taken to transfer the entire quantity of tablet powder into the bottle containing the syrup.
  4. Shake the bottle to wet the entire surface of the tablets. If the tablets have been crushed, shake the bottle until the endpoint is achieved.
  5. Allow the tablets to hydrate for at least two hours.
  6. After at least two hours have elapsed, shake the bottle intermittently over the course of at least another two hours until the tablets are completely disintegrated. NOTE: The tablets can be allowed to hydrate overnight to simplify the disintegration process.
The endpoint is achieved when a dispersion of fine particles in the syrup is obtained. This compounding procedure results in a solution containing 5 mg/mL of sotalol HCI. The fine solid particles are the water-insoluble inactive ingredients of the tablets. This extemporaneously prepared oral solution of sotalol HCI (with suspended inactive particles) must be shaken well prior to administration. This is to ensure that the amount of inactive solid particles per dose remains constant throughout the duration of use. Stability studies indicate that the suspension is stable for three months when stored at controlled room temperature (15°–30°C/59°–86°F) and ambient humidity. Transfer to Betapace (sotalol) AF from Betapace (sotalol) Patients with a history of symptomatic AFIB/AFL who are currently receiving Betapace (sotalol) for the maintenance of normal sinus rhythm should be transferred to Betapace (sotalol) AF because of the significant differences in labeling (i.e., patient package insert for Betapace (sotalol) AF, dosing administration, and safety information).

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Drugs undergoing CYP450 metabolism Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes. Antiarrhythmics Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with Betapace (sotalol) , because of their potential to prolong refractoriness (see WARNINGS). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with Betapace (sotalol) . Digoxin Single and multiple doses of Betapace (sotalol) do not substantially affect serum digoxin levels. Proarrhythmic events were more common in Betapace (sotalol) treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Calcium-blocking drugs Betapace (sotalol) should be administered with caution in conjunction with calcium-blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to hypotension. Catecholamine-depleting agents Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients treated with Betapace (sotalol) plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope. Insulin and oral antidiabetics Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked. Beta-2-receptor stimulants Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with Betapace (sotalol) . Clonidine Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving Betapace (sotalol) . Other No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin. Antacids Administration of Betapace (sotalol) within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it may result in a reduction in Cmax and AUC of 26% and 20%, respectively and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after Betapace (sotalol) has no effect on the pharmacokinetics or pharmacodynamics of sotalol. Drugs prolonging the QT interval Betapace (sotalol) should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see WARNINGS). Drug/Laboratory Test Interactions The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines.Read the Betapace Drug Interactions Center for a complete guide to possible interactions Learn More »

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Oral Betapace (sotalol hydrochloride) is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of Betapace (see WARNINGS), including a 1.5 to 2% rate of Torsade de Pointes or new VT/VF in patients with either NSVT or supraventricular arrhythmias, its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided. Initiation of Betapace (sotalol) treatment or increasing doses, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. The response to treatment should then be evaluated by a suitable method (e.g., PES or Holter monitoring) prior to continuing the patient on chronic therapy. Various approaches have been used to determine the response to antiarrhythmic therapy, including Betapace (sotalol) . In the ESVEM Trial, response by Holter monitoring was tentatively defined as 100% suppression of ventricular tachycardia, 90% suppression of nonsustained VT, 80% suppression of paired VPCs, and 75% suppression of total VPCs in patients who had at least 10 VPCs/hour at baseline; this tentative response was confirmed if VT lasting 5 or more beats was not observed during treadmill exercise testing using a standard Bruce protocol. The PES protocol utilized a maximum of three extrastimuli at three pacing cycle lengths and two right ventricular pacing sites. Response by PES was defined as prevention of induction of the following: 1) monomorphic VT lasting over 15 seconds; 2) non-sustained polymorphic VT containing more than 15 beats of monomorphic VT in patients with a history of monomorphic VT; 3) polymorphic VT or VF greater than 15 beats in patients with VF or a history of aborted sudden death without monomorphic VT; and 4) two episodes of polymorphic VT or VF of greater than 15 beats in a patient presenting with monomorphic VT. Sustained VT or NSVT producing hypotension during the final treadmill test was considered a drug failure. In a multicenter open-label long-term study of Betapace (sotalol) in patients with life-threatening ventricular arrhythmias which had proven refractory to other antiarrhythmic medications, response by Holter monitoring was defined as in ESVEM. Response by PES was defined as non-inducibility of sustained VT by at least double extrastimuli delivered at a pacing cycle length of 400 msec. Overall survival and arrhythmia recurrence rates in this study were similar to those seen in ESVEM, although there was no comparative group to allow a definitive assessment of outcome. Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias. Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name Betapace (sotalol) AF. Betapace (sotalol) is not approved for the AFIB/AFL indication and should not be substituted for Betapace (sotalol) AF because only BETAPACE (sotalol) AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

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Betapace (sotalol hydrochloride) is contraindicated in patients with bronchial asthma, sinus bradycardia, second and third degree AV block, unless a functioning pacemaker is present, congenital or acquired long QT syndromes, cardiogenic shock, uncontrolled congestive heart failure, and previous evidence of hypersensitivity to Betapace (sotalol) . Last reviewed on RxList: 3/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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Intentional or accidental overdosage with Betapace (sotalol hydrochloride) has rarely resulted in death. Symptoms and Treatment of Overdosage The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2-16 grams) of Betapace (sotalol) the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with Betapace (sotalol) should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels > 50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested: Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing. Heart Block: (second and third degree) transvenous cardiac pacemaker. Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful. Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant. Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

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Betapace (sotalol hydrochloride); capsule-shaped light-blue scored tablets imprinted with the strength and “Betapace (sotalol) ”, are available as follows: NDC 50419-105-10 80 mg strength, bottle of 100 NDC 50419-109-10 120 mg strength, bottle of 100 NDC 50419-106-10 160 mg strength, bottle of 100 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP Controlled Room Temperature]. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Manufactured in Finland. Rev. October 2010 Last reviewed on RxList: 3/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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Renal Impairment Betapace (sotalol hydrochloride) is mainly eliminated via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of Betapace (sotalol) . Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at 137-275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m²) or in mice, during a 24-month study at 4141-7122 mg/kg/ day (approximately 450-750 times the MRHD as mg/kg or 36-63 times the MRHD as mg/m²). Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity. No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/ day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/m²) prior to mating, except for a small reduction in the number of offspring per litter. Pregnancy Category B Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m²), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m²) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m²) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m²), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m²), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response. Although there are no adequate and well-controlled studies in pregnant women, sotalol HCl has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with Betapace (sotalol) . Therefore, Betapace (sotalol) should be used during pregnancy only if the potential benefit outweighs the potential risk. Nursing Mothers Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from Betapace (sotalol) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Betapace (sotalol) in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (See CLINICAL PHARMACOLOGY). Last reviewed on RxList: 3/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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